Autosomal Recessive Spinocerebellar Ataxia 16

Mendelian MONDO:0014339 Pathograph 77 Show in embeddings browser autosomal recessive cerebellar ataxia spinocerebellar ataxia

Autosomal recessive spinocerebellar ataxia 16 (SCAR16) is a progressive cerebellar degeneration caused by biallelic pathogenic variants in STUB1, which encodes CHIP (C-terminus of HSC70-interacting protein), a dimeric co-chaperone and U-box E3 ubiquitin ligase that couples the HSP70/HSC70 chaperone machinery to the ubiquitin-proteasome system. Disease variants have allele-dependent effects on CHIP structure, stability, chaperone interactions and ubiquitination. Some retain activity in individual biochemical assays, so a universal catalytic-null mechanism does not explain the disorder. The clinical core is progressive gait and limb ataxia with dysarthria and marked cerebellar atrophy on MRI. Pyramidal tract involvement (hyperreflexia, lower-limb spasticity) and cognitive decline are common accompanying features, and a subset of patients has hypogonadotropic hypogonadism, in which case the presentation corresponds to the historical Gordon Holmes syndrome. Dystonia, chorea and myoclonus broaden the movement-disorder phenotype in some patients; epilepsy can occur in infancy or accompany later multisystem disease. Age at onset is highly variable, spanning infancy to adulthood in the series that report it, and ataxia severity does not track age at onset. Heterozygous STUB1 variants cause the allelic autosomal dominant disorder SCA48 (MONDO:0032526), curated separately; recessive and dominant variants produce similar in vitro biochemical defects and the two entities form a clinical continuum rather than sharply separated diseases.

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Classifications

Harrison's Part

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Inheritance

Autosomal recessive inheritance HP:0000007

SCAR16 usually segregates as an autosomal recessive trait through homozygous or compound heterozygous pathogenic variants. A reported Gordon Holmes case had homozygous STUB1 c.612+11C>G in regions consistent with maternal uniparental isodisomy; the source classified that allele as a VUS, and the predicted splice effect remains unverified.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:24312598 SUPPORT Human Clinical

"In a two-generation autosomal recessive cerebellar ataxia family, we mapped a linkage to a minimal candidate region on chromosome 16p13.3"

Linkage in an autosomal recessive pedigree localizing the disease to the STUB1 locus.

PMID:24113144 SUPPORT Human Clinical

"We performed exome sequencing in a family with two of three siblings afflicted with ataxia and hypogonadism and identified a homozygous mutation in STUB1"

A homozygous variant segregating in affected siblings of unaffected parents is the recessive pattern.

url:https://www.def-lab.org/wp-content/uploads/2024/12/2024-Agianda-MDCP.pdf SUPPORT Human Clinical

"absence of heterozygosity on chromosome 16, consistent with UPiD(16)mat, covering a homozygous variant in STUB1."

Agianda et al. (PMID:39728009), author-hosted full text: The report supports the unusual route to homozygosity but does not establish pathogenicity of the intronic allele.

Discussions and Knowledge Gaps

By what cellular mechanism does loss of CHIP function produce hypogonadotropic hypogonadism, and why does it occur in only a subset of patients with biallelic STUB1 variants?

KNOWLEDGE GAP scar16_hypogonadism_mechanism

Attached to

pathophysiology#Hypothalamic-Pituitary Gonadotropin Deficiency

The original sisters retained GnRH-stimulated gonadotropin responses, suggesting a hypothalamic contribution without excluding later pituitary dysfunction. Patient-fibroblast signaling studies do not establish endocrine-cell causation. Why hypogonadism occurs in only some STUB1 families remains unresolved.

Show evidence (1 reference)

PMID:24742043 SUPPORT Human Clinical

"Cognitive impairment was present only in one and hypogonadism in none of them."

The cohort observation that makes the gap concrete: unbiased screening found no hypogonadism at all, against a literature in which it defines the syndrome.

Is the impaired heat-shock response seen in SCAR16 patient fibroblasts relevant to the neurodegeneration, given that patient iPSC-derived cortical neurons do not show it?

HUMAN MODEL MISMATCH scar16_heat_shock_response_translational_validity

Attached to

pathophysiology#Failure of Chaperone-Assisted Protein Quality Control

Evidence exists in a model system and its translational validity is the open question, which is the HUMAN_MODEL_MISMATCH case rather than a plain absence of evidence. Patient fibroblasts show impaired heat-shock response induction and recovery, but patient cortical neurons were resistant to heat stress with high basal HSP70, and an isogenic CRISPR STUB1 knockout neuron line behaved like the patient lines, so the neuronal readout does not separate mutant from null from control. The authors themselves question whether impaired heat-shock response has any role in SCAR16 neuropathology. Since the disease target tissue is neuronal, the fibroblast finding cannot stand as the disease mechanism, and the proteostasis node here rests on the ubiquitination and mitophagy evidence rather than on the heat-shock arm.

Show evidence (1 reference)

PMID:33097556 SUPPORT In Vitro

"Furthermore, STUB1(-/-) neurons generated by CRISPR/Cas9-mediated genome editing from an isogenic healthy control line showed a similar HSR to patients."

The isogenic knockout behaving like the patient lines is what removes the neuronal heat-shock readout's ability to discriminate, and is the specific result the mismatch turns on.

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Pathophysiology

Biallelic STUB1 Loss-of-Function Variants

Homozygous or compound heterozygous pathogenic variants in STUB1 are the initiating lesion. Variants are distributed across all three CHIP domains (tetratricopeptide-repeat, coiled-coil and U-box) and include missense, nonsense and frameshift alleles; a nonsense allele truncates the protein before the U-box and abolishes ligase activity outright.

STUB1 hgnc:11427

Downstream

CHIP Structural Destabilization

Loss of CHIP E3 Ubiquitin Ligase Activity

Impaired CHIP-HSC70 Chaperone Coupling

CARP-Dependent CHIP Aggregate Formation

Show evidence (2 references)

PMID:24312598 SUPPORT Human Clinical

"using a combination of whole-exome sequencing and linkage analysis, we identified CHIP, encoding a U-box containing ubiquitin E3 ligase, as a novel causative gene for autosomal recessive cerebellar ataxia."

The gene-discovery study establishing STUB1/CHIP as the cause of this autosomal recessive cerebellar ataxia.

PMID:28396517 SUPPORT In Vitro

"Spinocerebellar ataxia, autosomal recessive 16 (SCAR16) is caused by biallelic mutations in the STIP1 homology and U-box containing protein 1 (STUB1) gene encoding the ubiquitin E3 ligase and dimeric co-chaperone C-terminus of Hsc70-interacting protein (CHIP)."

States the biallelic requirement and identifies the gene product as a dual-function E3 ligase and co-chaperone.

CHIP Structural Destabilization

Many tested SCAR16 variants reduce CHIP thermal stability. The p.Thr246Met U-box is structurally disorganized, whereas p.Asn65Ser has increased alpha-helical content and resistance to limited proteolysis in the 2017 study. Effects vary with allele, assay and construct; several 2017 structural experiments used an MBP fusion. Reduced steady-state abundance in cells is a distinct accompanying observation, not proof that every allele is equally unstable.

Experimental models

Temperature-dependent CHIP missense-variant assays OTHER Most variants showed destabilization and soluble oligomer formation; effects varied across assays and alleles.

Downstream

Loss of CHIP E3 Ubiquitin Ligase Activity

CHIP Oligomerization

Reduced CHIP Protein Abundance

Show evidence (3 references)

PMID:29317501 SUPPORT In Vitro

"This destabilization caused mutation-specific defects in CHIP activity, including increased formation of soluble oligomers, decreased interactions with chaperones, diminished substrate ubiquitination, and reduced steady-state levels in cells."

Enumerates the consequences of destabilization that this node describes: oligomer formation, weakened chaperone interaction, less substrate ubiquitination, and lower protein abundance.

PMID:28396517 SUPPORT In Vitro

"our results illustrate that some STUB1 mutations known to cause recessive SCAR16 have a profound impact on the protein structure, stability, and ability of CHIP to dimerize in vitro."

Independent biophysical characterization of six SCAR16 variants confirming effects on structure, stability and dimerization.

PMID:28396517 SUPPORT In Vitro

"N65S shows increased CHIP dimerization, higher levels of α-helical content, and decreased degradation rate compared with wild-type (WT) CHIP."

This allele was more resistant to limited proteolysis, contrasting with the aggregation-prone T246M protein.

Reduced CHIP Protein Abundance

CHIP steady-state protein levels are reduced in several patient fibroblast and mutant-expression systems, and in T246M rodent tissues. The effect varies across alleles and constructs; measured abundance does not itself identify the degradation pathway.

Animal models

CHIP T246M-equivalent knock-in rat Rat partially recapitulates CHIP protein abundance is reduced in cerebellum, whole brain and testes and declines further with age; reduced tissue abundance is the modeled component.

Downstream

Failure of Chaperone-Assisted Protein Quality Control Reduced protein availability can contribute to the patient-fibroblast proteostasis defect; mutant abundance and mutant activity were not independently varied.

Excess PINK1/Parkin-Mediated Mitophagy CHIP knockdown produces the mitophagy phenotype in stressed U2OS/Parkin cells. Transfer to biallelic SCAR16 neurons remains hypothetical.

Show evidence (1 reference)

PMID:25258038 SUPPORT In Vitro

"Furthermore, we show that the levels of CHIP are strongly reduced in vivo in patients' fibroblasts compared to controls."

Confirms in patient-derived cells that CHIP protein abundance is reduced, not only that the enzyme is catalytically impaired.

CHIP Oligomerization

Many recombinant SCAR16 proteins form higher-order soluble assemblies. This is allele-dependent: p.Asn65Ser remained predominantly dimeric in the 2018 study. Soluble oligomers and detergent-insoluble aggregates are separate experimental readouts. The experiments do not isolate oligomerization as the cause of a particular downstream patient phenotype.

Show evidence (1 reference)

PMID:29317501 SUPPORT In Vitro

"increased formation of soluble oligomers"

The biochemical study measured increased soluble oligomers; this is distinct from insoluble cellular inclusions.

CARP-Dependent CHIP Aggregate Formation

Mechanism confidence: Provisional

CARP-mediated CHIP ubiquitination favors detergent-insoluble sequestration. The T246M protein shows greater insoluble accumulation than wild type during CARP2 coexpression. This cellular mechanism has not been established in patient neurons. Whether this sequestration causes neuronal injury or is protective is unresolved.

Experimental models

CARP-dependent CHIP sequestration in HEK293T and N2A cells CELL LINE CARP expression promotes CHIP sequestration into insoluble material.

Show evidence (1 reference)

PMID:36853170 SUPPORT In Vitro

"pathogenic mutants of STUB1 are more prone than the wild-type to CARP2-mediated aggregate assembly."

CARP2 modifies mutant CHIP and promotes aggregate assembly in experimental systems; human neuronal causation is untested.

Loss of CHIP E3 Ubiquitin Ligase Activity

Loss or reduction of ubiquitin ligase activity is allele- and assay-dependent. p.Thr246Met abolishes Hsc70- and self-ubiquitination while retaining chaperone interactions, but also destabilizes and oligomerizes CHIP. In the 2017 recombinant assays, p.Asn65Ser retained self-ubiquitination with impaired Hsc70 ubiquitination, whereas p.Glu28Lys, p.Lys145Gln, p.Met211Ile and p.Ser236Thr had activity similar to wild type. Preserved activity in one assay does not exclude defective cellular abundance, structure or handling of other substrates.

protein ubiquitination GO:0016567 ↓ DECREASED

ubiquitin-protein transferase activity GO:0004842 ⇓ LOSS OF FUNCTION

Experimental models

Recombinant CHIP disease-variant biochemistry OTHER Reproduces substrate-ubiquitination defects for N65S and T246M, while four other variants retain wild-type-like activity in these assays.

STUB1 truncation constructs in SH-SY5Y and HEK293T cells CELL LINE The p.Gln118Ter construct produced truncated CHIP with reduced Hsc70 polyubiquitination.

HEK293 CHIP-Fbx2 NR2A-turnover reconstitution CELL LINE Disease variants failed to support the wild-type CHIP/Fbx2 effect on NR2A turnover.

Downstream

Failure of Chaperone-Assisted Protein Quality Control

Impaired PKAc Ubiquitination and Turnover

Impaired NEK10 Proteolysis

PDE9A Accumulation Impaired CHIP-dependent substrate ubiquitination diminishes PDE9A clearance.

Show evidence (2 references)

PMID:30222779 SUPPORT In Vitro

"We discovered a genetic disease, now known as spinocerebellar autosomal recessive 16 (SCAR16), resulting from a coding mutation that caused a loss of CHIP ubiquitin ligase function."

The discovery work concerns the p.Thr246Met allele; it does not establish complete catalytic loss for every SCAR16 allele.

PMID:28396517 REFUTE In Vitro

"The ubiquitination activities of the other mutants (E28K, K145Q, M211I, and S236T) were not overtly different from WT CHIP."

Recombinant Hsc70- and self-ubiquitination assays retain activity for these alleles, refuting a universal catalytic-null model.

Impaired CHIP-HSC70 Chaperone Coupling

Some variants impair CHIP interactions with HSP70/HSC70 or handling of the chaperone substrate. Effects differ among TPR variants: p.Asn65Ser retains self-ubiquitination but has impaired Hsc70 ubiquitination, whereas p.Glu28Lys retains both activities in the 2017 assays. The U-box p.Thr246Met protein retains chaperone binding despite loss of ligase activity. These observations separate chaperone coupling from catalytic activity without making all variants in one domain functionally equivalent.

Hsp70 protein binding GO:0030544 ↓ DECREASED protein-folding chaperone binding GO:0051087 ↓ DECREASED

Downstream

Failure of Chaperone-Assisted Protein Quality Control

Show evidence (3 references)

PMID:25258038 SUPPORT In Vitro

"We show that the p.Asn65Ser substitution impairs CHIP's ability to ubiquitinate HSC70 in vitro, despite being able to self-ubiquitinate."

A tetratricopeptide-repeat variant that specifically fails to handle the chaperone substrate while retaining self-ubiquitination is the direct demonstration that this arm of the mechanism is separable from the catalytic arm.

PMID:29317501 SUPPORT In Vitro

The decreased-chaperone-interaction clause is what supports the reduced binding recorded in this node's molecular_functions; the neighbouring clauses about oligomers and abundance belong to the destabilization node and are curated there.

PMID:24742043 SUPPORT Human Clinical

"Our results expand the genotypic spectrum of STUB1-disease, showing that pathogenic mutations affect also the tetratricopeptide-repeat domain, thus providing clinical evidence for the functional importance of this domain."

Establishes that the chaperone-binding TPR domain carries pathogenic variants in patients, so this arm of the mechanism is clinically instantiated and not only a biochemical possibility.

Failure of Chaperone-Assisted Protein Quality Control

Defective CHIP-dependent client handling and ubiquitination can disrupt protein turnover. Patient fibroblasts show altered heat-shock responses; patient-derived immature cortical neurons instead show proteomic pathway differences without reproducing the fibroblast response defect. These assays do not establish uniform impairment across alleles, cell types or developmental stages. A separate proposed mitophagy mechanism rests on gene perturbation and SCA48-variant models rather than direct SCAR16 evidence.

protein quality control for misfolded or incompletely synthesized proteins GO:0006515 ↓ DECREASED ubiquitin-dependent protein catabolic process GO:0006511 ↓ DECREASED

Experimental models

SCAR16 patient primary fibroblasts PRIMARY CELL CULTURE Patient fibroblasts show impaired heat-shock response induction and recovery, a cellular readout of disturbed proteostasis.

SCAR16 patient iPSC-derived cortical neurons IPSC DERIVED MODEL Proteomic enrichment patterns were consistent with altered protein folding and oxidative-stress responses in patient cortical neurons. These are proteomic inferences rather than direct measurements of protein-refolding capacity or reactive oxygen species.

SCAR16 p.Met211Ile/p.Glu238Ter patient fibroblasts under proteasome stress PRIMARY CELL CULTURE Patient fibroblasts showed stress-associated cell injury, protein ubiquitination and autophagy abnormalities, with improvement in several readouts after trehalose.

Animal models

Chip U-box truncation zebrafish Zebrafish partially recapitulates Whole-brain 26S proteasome activity was reduced at 24 months, but not at 6 months, when Purkinje-cell counts were already reduced. The timing does not establish this measured decline as the initiating cause of cell loss.

Downstream

Corticospinal Tract Involvement

Hypothalamic-Pituitary Gonadotropin Deficiency

Purkinje Cell Degeneration In the zebrafish truncation model, Purkinje-cell counts were already reduced at 6 months, while the measured whole-brain proteasome decline appeared only at 24 months; this experiment does not resolve the initiating causal step.

Show evidence (2 references)

PMID:33097556 SUPPORT In Vitro

"We found impaired HSR induction and recovery compared to healthy controls."

Primary fibroblasts from three SCAR16 patients show a defective heat shock response, a direct patient-cell readout of disturbed proteostasis.

PMID:33097556 SUPPORT In Vitro

"Proteomic analysis of CNs showed dysfunctional protein (re)folding and higher basal oxidative stress levels in patients."

Protein-abundance and pathway-enrichment differences in patient-derived cortical neurons support altered proteostasis responses. The full text reports proteomic inference rather than direct measurement of refolding capacity or reactive oxygen species.

Purkinje Cell Degeneration

Cerebellar Purkinje neurons are a major cellular target. Autopsy of a man with compound heterozygous p.Met211Ile/p.Glu238Ter STUB1 variants showed severe Purkinje and granule-cell loss with Bergmann gliosis. Experimental U-box truncation also affects Purkinje-cell number, size and dendritic organization.

Purkinje cell CL:0000121

Animal models

Chip U-box truncation zebrafish Zebrafish partially recapitulates Purkinje-cell body counts were reduced at 6 and 24 months; cell-body area was reduced at 24 months. Dendritic organization was abnormal, with increased spine counts significant at 6 months only.

CHIP T246M knock-in mouse Mouse partially recapitulates Aged knock-in mice show reduced CHIP staining and loss of calbindin-positive Purkinje cells; Figure 5H examines 52-week-old animals.

CHIP T246M-equivalent knock-in rat Rat partially recapitulates At 32 weeks, rat cerebellar sections show reduced calbindin staining and fewer Purkinje cells.

Downstream

Cerebellar Atrophy

Show evidence (3 references)

url:https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf SUPPORT Human Clinical

"severe loss of Purkinje cells and neurons of the granular layer, accompanied by reactive Bergmann gliosis"

Bettencourt 2015 (PMID:25592071), recovered full text: Direct autopsy evidence in biallelic recessive SCAR16; this finding does not require inference from SCA48.

PMID:34630034 SUPPORT Model Organism

"In contrast to SCAR16/SCA48 patients, no gross cerebellar atrophy was evident in mutant fish, however, these fish displayed reduced numbers and sizes of Purkinje cell bodies and abnormal organization of Purkinje cell dendrites."

Direct demonstration that loss of Chip U-box function damages Purkinje cells. The same sentence records that gross cerebellar atrophy was absent in this model, so the model supports the cellular node without supporting the tissue-level one.

PMID:34630034 SUPPORT Model Organism

"In the brain, stub1 mRNA was predominantly detected in the cerebellum, including the Purkinje cell layer and granular layer."

The gene is expressed in the Purkinje layer that degenerates, which is consistent with a cell-autonomous lesion. Expression is not degeneration: the granular layer also expresses stub1 and no granule-cell loss is reported, which is why only the Purkinje cell is bound above.

Cerebellar Atrophy

Cerebellar volume loss is a characteristic MRI finding in reported SCAR16 cohorts. Brainstem or more widespread abnormalities occur in some patients; their presence is not required for diagnosis.

cerebellum UBERON:0002037

Downstream

Progressive Cerebellar Ataxia

Dysarthria

Gait Ataxia

Nystagmus

Cerebellar Atrophy on MRI

Show evidence (3 references)

PMID:33417001 SUPPORT Human Clinical

"Brain MRI showed marked cerebellar atrophy in all patients."

Cerebellar atrophy in every patient of a French series that included four SCAR16 cases.

PMID:32367277 SUPPORT Human Clinical

"The brain MRIs showed a marked cerebellar atrophy of the patients."

Independent confirmation in the Taiwanese SCAR16 families.

PMID:36569391 SUPPORT Human Clinical

"An MRI of her brain showed moderate to severe atrophy of the cerebellum and brainstem."

A radiologically characterized SCAR16 case showing that the atrophy can extend beyond the cerebellum to the brainstem.

Corticospinal Tract Involvement

Pyramidal tract damage accompanies the cerebellar degeneration in a large share of patients, producing hyperreflexia and, at the more severe end, lower-limb spasticity or spastic tetraparesis. It is frequent enough that STUB1 disease belongs in the differential diagnosis of the spastic ataxias.

Downstream

Hyperreflexia

Lower Limb Spasticity

Spastic Tetraparesis

Show evidence (2 references)

PMID:24742043 SUPPORT Human Clinical

"All patients showed evidence of pyramidal tract damage."

Every STUB1 ataxia patient in this Caucasian screening cohort had pyramidal tract involvement.

PMID:28193273 SUPPORT Human Clinical

"All three subjects presented with a severe multisystemic phenotype including severe dementia, spastic tetraparesis, epilepsy, and autonomic dysfunction in addition to cerebellar ataxia, plus hypogonadism in one index patient."

Documents spastic tetraparesis as the severe end of the corticospinal involvement, alongside the other multisystem features.

Hypothalamic-Pituitary Gonadotropin Deficiency

A subset of patients has hypogonadotropic hypogonadism, the feature that made the historical Gordon Holmes syndrome. Loss of CHIP function reproduces reproductive as well as motor impairment in mice, but the cellular basis of the neuroendocrine deficit in human disease has not been established, and hypogonadism is absent from whole cohorts of STUB1 ataxia. In the original T246M sisters, preserved responses to a single GnRH challenge suggested a hypothalamic contribution, but did not exclude later pituitary dysfunction.

Downstream

Hypogonadotropic Hypogonadism

Show evidence (3 references)

PMID:24113144 SUPPORT Model Organism

"Loss of CHIP function in mice resulted in behavioral and reproductive impairments that mimic human ataxia and hypogonadism."

Mouse loss of CHIP function produces reproductive impairment alongside the behavioural phenotype, supporting a causal rather than coincidental link between the CHIP defect and the gonadal axis.

PMID:28193273 SUPPORT Human Clinical

"our data reveal the second STUB1 family with ataxia plus hypogonadism reported so far, demonstrating that Gordon Holmes syndrome is indeed a recurrent manifestation of STUB1."

Confirms in patients that the ataxia-plus-hypogonadism combination recurs in STUB1 disease rather than being confined to the index family.

PMID:24742043 SUPPORT INDIRECT Human Clinical

"In contrast to previous reports, STUB1-ataxia can start even above age 40 years, and neither hypogonadism nor prominent cognitive impairment are obligatory features."

Supports this node's framing as a subset branch rather than an obligatory part of SCAR16: a screening cohort found no hypogonadism at all. Indirect because the quote establishes the branch's optionality by absence rather than asserting the branch itself.

Excess PINK1/Parkin-Mediated Mitophagy

Mechanism confidence: Hypothetical

CHIP knockdown increases stress-induced PINK1 abundance, Parkin recruitment and mitochondrial delivery to lysosomes in U2OS cells engineered to express Parkin. Loss of the worm orthologue chn-1 increases basal neuronal mitophagy, dependent on pink-1 and pdr-1. Whether this mechanism contributes to SCAR16 Purkinje-cell disease is unconfirmed: the two patient variants tested in the 2024 study, p.Ile53Thr and p.Leu275AspfsTer16, are dominant SCA48 alleles, not recessive SCAR16 alleles. A separate 2025 T246M rat study interprets mitochondrial morphology and static autophagy markers as impaired mitophagy; these assays and genotypes differ and do not establish a single direction of flux across models.

mitophagy GO:0000423 ↑ INCREASED

Experimental models

CHIP-perturbed U2OS Parkin mitophagy reporter cells CELL LINE CHIP knockdown increases stress-induced mitophagy; wild-type CHIP overexpression suppresses it.

Animal models

chn-1 loss-of-function worm mitophagy reporters Caenorhabditis elegans perturbs Loss of chn-1 increases basal neuronal mitochondrial delivery to lysosomes.

Show evidence (2 references)

url:https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf SUPPORT INDIRECT In Vitro

"CHIP knockdown significantly increased the percentage of cells undergoing mitophagy"

Earnshaw et al. 2024 (PMID:39117117), recovered full text: The U2OS result required CCCP-induced mitochondrial stress and ectopic Parkin; extrapolation to SCAR16 is indirect.

url:https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf SUPPORT INDIRECT Model Organism

"the increase in neuronal mitophagy observed in chn-1(by155) worms is dependent on both PINK1 and Parkin."

Earnshaw et al. 2024 (PMID:39117117), recovered full text: Loss-of-function and double-mutant comparisons support the pathway in worm neurons, not its causal role in human SCAR16.

Impaired PKAc Ubiquitination and Turnover

Mechanism confidence: Provisional

CHIP-dependent ubiquitination and proteasomal turnover of activated PKA catalytic subunits are impaired by CHIP loss in cell models. PKAc Lys310 is the principal ubiquitin acceptor identified in the 2019 study. This substrate-specific regulatory mechanism is distinct from clearance of misfolded proteins; its downstream signaling defect is observed in SCAR16 fibroblasts.

protein ubiquitination GO:0016567 ↓ DECREASED

Downstream

Elevated Basal PKA-CREB Signaling

Show evidence (1 reference)

PMID:31189917 SUPPORT In Vitro

"CHIP knockdown prevented PKAc decline following holoenzyme dissociation."

HEK293 perturbation experiments establish CHIP-dependent PKAc turnover; patient fibroblasts establish the downstream signaling phenotype rather than directly measuring this degradation step.

Elevated Basal PKA-CREB Signaling

Mechanism confidence: Provisional

SCAR16 patient fibroblasts have elevated basal CREB phosphorylation with little additional response to forskolin. PKA inhibition reduces this phosphorylation phenotype. CHIP perturbation and hippocampal slice studies support a signaling role, but these experiments do not prove that this pathway causes human Purkinje-cell loss or hypogonadism. The measured fibroblast signaling state has not been linked causally to an individual SCAR16 clinical manifestation.

Experimental models

SCAR16 AX71 and AX29 fibroblast PKA-signaling assays PRIMARY CELL CULTURE Increased basal CREB phosphorylation and blunted further induction by forskolin model defective signaling attenuation.

Show evidence (2 references)

PMID:31189917 SUPPORT In Vitro

"STUB1 mutations, like CHIP downregulation, increased basal levels of phosphoCREB-positive nuclei that could not be further induced by FSK."

Primary fibroblasts from two SCAR16 patients, AX71 and AX29, show altered basal signaling and response to forskolin. These are cell-culture readouts, not clinical biomarkers.

PMID:31189917 SUPPORT In Vitro

"In SCAR16 fibroblasts, inhibition of PKA activity reversed the effects of CHIP mutations on CREB phosphorylation"

H89 reverses a biochemical patient-cell readout; clinical efficacy was not investigated.

Impaired NEK10 Proteolysis

Mechanism confidence: Provisional

Cellular CHIP deficiency interferes with degradation of the pro-ciliogenic kinase NEK10. In the reconstructed pathway, PKA phosphorylation of NEK10 at T812 primes its CHIP-dependent ubiquitination and proteolysis. The pathway is supported by HEK293 perturbations and by downstream ciliary phenotypes in SCAR16 fibroblasts.

protein ubiquitination GO:0016567 ↓ DECREASED

Downstream

Impaired cAMP-Induced Cilium Resorption

Show evidence (2 references)

PMID:29581457 SUPPORT In Vitro

"wild-type CHIP, but not its catalytically inactive mutant (K30A), reduced NEK10 levels"

HEK293 biochemical experiments place CHIP downstream of PKA phosphorylation of NEK10 at T812. K30A is an experimental chaperone-binding mutant, not a patient allele.

PMID:29581457 SUPPORT In Vitro

"genetic silencing of endogenous CHIP (Fig. 6f) prevented FSK-induced NEK10 poly-ubiquitination."

Endogenous CHIP knockdown supports the same substrate-ubiquitination dependence as the K30A construct.

Impaired cAMP-Induced Cilium Resorption

Mechanism confidence: Provisional

Serum-starved SCAR16 AX71 fibroblasts show impaired primary-cilium resorption after forskolin stimulation. NEK10 knockdown reduces their ciliated-cell fraction. The finding depends on culture conditions; the study reports different cAMP effects in serum-supplemented confluent cells. Its contribution to human neurological or endocrine disease remains unresolved. A causal contribution of this fibroblast ciliary phenotype to cerebellar degeneration has not been demonstrated.

cilium disassembly GO:0061523 ↓ DECREASED

Experimental models

SCAR16 AX71 fibroblast cilium-resorption assay PRIMARY CELL CULTURE Cilia persist after forskolin in the patient-cell assay, whereas control cells undergo resorption.

Show evidence (1 reference)

PMID:29581457 SUPPORT In Vitro

"no major effects of FSK stimulation on cilia were evident in SCAR16 fibroblasts."

Under serum starvation, control fibroblasts resorb cilia after forskolin, whereas the SCAR16 AX71 model does not. This does not establish a clinical ciliopathy diagnosis.

PDE9A Accumulation

Mechanism confidence: Provisional

PDE9A protein accumulates in the homozygous T246M rat model and CHIP-perturbed HEK293T cells. CHIP normally promotes K63- and K27-linked ubiquitination of PDE9A at Lys186 and its autophagic clearance. The 2025 study supports this substrate-specific pathway as a candidate contributor to SCAR16, without human patient confirmation.

protein ubiquitination GO:0016567 ↓ DECREASED

Experimental models

HEK293T CHIP-PDE9A ubiquitination and turnover assays CELL LINE Substrate-site and CHIP perturbations test the ubiquitination-dependent control of PDE9A abundance.

Animal models

CHIP T246M rat PDE9A intervention cohorts Rat partially recapitulates Increased PDE9A protein accompanies reduced CHIP in mutant cerebellar and hippocampal tissue.

Downstream

Reduced cGMP Availability PDE9A-mediated cGMP hydrolysis provides the proposed biochemical link.

Mitochondrial Structural Injury PDE9A inhibition improves mitochondrial injury in the mutant rat; the intervening causal steps are not isolated by these experiments.

Show evidence (2 references)

PMID:39806097 SUPPORT In Vitro

"Mutation of PDE9A at K186R disrupted CHIP-mediated ubiquitination, resulting in an increased half-life and overaccumulation of PDE9A in cells"

Substrate-site mutagenesis connects ubiquitination to PDE9A turnover. Bafilomycin and bortezomib comparisons support autophagic rather than proteasomal degradation of PDE9A in this system.

PMID:39806097 SUPPORT Model Organism

"the levels of CHIP, cGMP, PKG1 and PKG2 were diminished in the Hom group, and the PDE9A level was increased"

Rat cerebellar and hippocampal measurements include cGMP ELISA and protein assays. These establish the model state; they are not patient biomarker measurements.

Reduced cGMP Availability

Mechanism confidence: Provisional

cGMP concentrations are reduced in cerebellar and hippocampal tissue of homozygous T246M rats. Reduced PKG1/PKG2 abundance and transcriptomic pathway scores accompany this state. These measurements should not be equated with direct PKG enzyme-activity assays.

Animal models

CHIP T246M rat PDE9A intervention cohorts Rat partially recapitulates Tissue cGMP concentrations are reduced in mutant rats and improve after treatment.

Downstream

Reduced CHIP Serine Phosphorylation The proposed cGMP-PKG pathway links PDE9A inhibition to restored CHIP phosphorylation.

Show evidence (1 reference)

PMID:39806097 SUPPORT Model Organism

"the levels of CHIP, cGMP, PKG1 and PKG2 were diminished in the Hom group, and the PDE9A level was increased"

Rat cerebellar and hippocampal measurements include cGMP ELISA and protein assays. These establish the model state; they are not patient biomarker measurements.

Reduced CHIP Serine Phosphorylation

Mechanism confidence: Provisional

CHIP phosphorylation at the rodent Ser20 site is reduced in the T246M rat model and increases after PDE9A inhibition or AAV-CHIP treatment. This corresponds to human Ser19. The study proposes reduced phosphorylation-dependent CHIP stability as a reinforcing feedback loop; relevance across the human allelic spectrum remains untested.

Downstream

Reduced CHIP Protein Abundance Proposed positive feedback in the rat study; the phosphorylation and stability steps have not been isolated across SCAR16 patient alleles.

Show evidence (1 reference)

PMID:39806097 SUPPORT Model Organism

"After the inhibition of PDE9A with Bay 73-6691, a conspicuous increase in CHIP S20 phosphorylation was detected"

The phospho-specific antibody detects the rodent S20 site, corresponding to human S19. Inhibitor and AAV interventions support the feedback model.

Mitochondrial Structural Injury

Mechanism confidence: Provisional

T246M rat cerebellar tissue shows swollen mitochondria, cristae disruption and vacuolization. Increased p62 and FIS1 and reduced LC3B, OPA1 and BNIP3 accompany the ultrastructural injury. PDE9A inhibition or CHIP gene delivery improves these readouts. The authors interpret them as disturbed mitophagy, but the study does not directly quantify mitophagic flux; it therefore does not settle the direction of mitochondrial clearance in human SCAR16. The experiments do not isolate this structural injury as the cause of Purkinje-cell loss.

Animal models

CHIP T246M rat PDE9A intervention cohorts Rat partially recapitulates Mitochondrial ultrastructural injury improves after BAY 73-6691 or AAV-CHIP treatment.

Show evidence (2 references)

PMID:39806097 SUPPORT Model Organism

"Treatment with Bay 73-6691 or AAV-CHIP resulted in a reduction in scores, indicating mitigated mitochondrial damage and morphological improvements in the mutated rats"

Electron microscopy and Flameng scoring establish mitochondrial structural injury and its improvement in the treated rat cohorts. Static morphology and marker levels do not directly measure mitophagic flux.

PMID:39806097 SUPPORT Model Organism

"increased P62 and decreased LC3B levels were detected in both the hippocampus and cerebellum"

The measured static markers support altered autophagy-associated states, not a direct rate measurement.

✶

Histopathology

Cerebellar cortical neuronal loss with Bergmann gliosis

Autopsy of one man with p.Met211Ile/p.Glu238Ter STUB1 variants showed severe Purkinje-cell and granule-layer neuronal loss with reactive Bergmann gliosis. This is a direct recessive-disease observation; its prevalence across SCAR16 is unknown.

Show evidence (1 reference)

url:https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf SUPPORT Human Clinical

"severe loss of Purkinje cells and neurons of the granular layer, accompanied by reactive Bergmann gliosis"

Bettencourt 2015 (PMID:25592071), recovered full text: Defines the neuronal populations lost and the associated reactive gliosis.

p62-positive neuronal intranuclear inclusions

A few p62-positive neuronal intranuclear inclusions were reported in frontal cortex and caudate in the same p.Met211Ile/p.Glu238Ter autopsy. This single-case finding does not establish a universal or diagnostic inclusion pathology.

Show evidence (1 reference)

url:https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf SUPPORT Human Clinical

"P62-antibody stained a few neuronal intra nuclear inclusions in small neurons of frontal cortex and caudate"

Bettencourt 2015 (PMID:25592071), recovered full text: Describes the sparse inclusions and their location in the recessive case.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Digestive 1

Dysphagia HP:0002015

Show evidence (2 references)

PMID:28193273 SUPPORT Human Clinical

"necessitating gastric tube feeding in both subjects from family 2 at the age of 36 and 43, respectively."

All three recessive cases developed severe dysphagia; two required enteral feeding.

url:https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf SUPPORT Human Clinical

"severe neurogenic dysphagia, which led to aspiration pneumonia and death."

Bettencourt 2015 (PMID:25592071), recovered full text: The proband developed severe dysphagia late in the course; this supplies direct recessive-case evidence.

Ear 1

High-Frequency Sensorineural Hearing Impairment HP:0001757

Show evidence (1 reference)

PMID:25258038 SUPPORT Human Clinical

"Pure tone audiometry indicated very mild sensorineural hearing loss in the high frequencies"

Audiometry in the younger sister documented this finding, comparable to the result in her brother.

Endocrine 1

Hypogonadotropic Hypogonadism HP:0000044

Show evidence (4 references)

PMID:25258038 SUPPORT Human Clinical

"secondary infertility due to hypogonadotrophic hypogonadism."

A woman with p.Glu28Lys/p.Lys144Ter developed secondary infertility before progressive adult-onset ataxia.

PMID:32367277 SUPPORT INDIRECT Other

"Mutations in STUB1 have been identified to cause autosomal recessive spinocerebellar ataxia type 16 (SCAR16), also named as Gordon Holmes syndrome, which is characterized by cerebellar ataxia, cognitive decline, and hypogonadism."

A nosological definition of the entity, not an observation: this is the paper's background sentence, and its own three patients had no hypogonadism. Graded OTHER and INDIRECT because it establishes that hypogonadism belongs to the recognized SCAR16 description, not that any patient in this study had it.

PMID:42080998 SUPPORT Human Clinical

"Hypogonadotrophic hypogonadism were seen in all variants."

In the published Gordon Holmes syndrome case series, hypogonadotropic hypogonadism occurred across every causal gene including STUB1. Note that this review is ascertained on the Gordon Holmes phenotype, so it speaks to the hypogonadism-defined subset, not to unselected SCAR16.

+ 1 more reference

Eye 2

Nystagmus HP:0000639

Show evidence (1 reference)

PMID:25258038 SUPPORT Human Clinical

"Horizontal nystagmus; mild retinal atrophy"

Table 1 records horizontal nystagmus in the index brother and younger sister; no population frequency is inferred.

Juvenile Cataract HP:0001118

Show evidence (1 reference)

PMID:28193273 SUPPORT Human Clinical

"cataracts requiring surgery at the age of 11."

The clinical narrative documents childhood cataract in one recessive case.

Musculoskeletal 2

Lower Limb Spasticity HP:0002061

Show evidence (2 references)

PMID:24742043 SUPPORT Human Clinical

"Pyramidal tract damage is a common accompanying feature and can include lower limb spasticity"

States that the pyramidal involvement can extend to lower-limb spasticity.

PMID:28193273 SUPPORT Human Clinical

Records spastic tetraparesis, the severe end of the same spectrum, in all three subjects of the multisystemic STUB1 families.

Spastic Tetraparesis HP:0001285

Show evidence (1 reference)

PMID:28193273 SUPPORT Human Clinical

"All three subjects presented with a severe multisystemic phenotype including severe dementia, spastic tetraparesis"

The abstract and full clinical results document four-limb spastic impairment in the three recessive patients.

Nervous System 15

Progressive Cerebellar Ataxia VERY_FREQUENT HP:0002073

Course: PROGRESSIVE Onset: JUVENILE; 0.5-49.0y

Sequelae: Dysarthria

Show evidence (5 references)

PMID:33417001 SUPPORT Human Clinical

"Here, we report four SCAR16 and nine SCA48 patients from two SCAR16 and five SCA48 unrelated French families. All presented with slowly progressive cerebellar ataxia."

All thirteen patients, including the four SCAR16 cases, had slowly progressive cerebellar ataxia, supporting the VERY_FREQUENT band.

PMID:29317501 SUPPORT Other

"in humans, mutations in CHIP cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16), a fatal neurodegenerative disease characterized by truncal and limb ataxia that results in gait instability"

Characterizes the disease by truncal and limb ataxia producing gait instability, which is the phenotype described here.

PMID:33417001 SUPPORT Human Clinical

"The age at onset was highly variable, ranging from 14 to 76 years."

Documents how wide the onset range runs across STUB1 disease. It is not used to set this entry's recorded range because the cohort combines SCAR16 and SCA48 patients.

+ 2 more references

Gait Ataxia VERY_FREQUENT HP:0002066

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:29317501 SUPPORT Other

"characterized by truncal and limb ataxia that results in gait instability"

Names gait instability as the functional consequence characterizing the disease.

Dysarthria HP:0001260

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:42080998 SUPPORT Human Clinical

"Cerebellar ataxia and dysarthria were seen in all variants."

A review of published Gordon Holmes syndrome cases, including the five with STUB1 variants, found dysarthria in every genetic subgroup.

Cerebellar Atrophy on MRI VERY_FREQUENT HP:0001272

Course: PROGRESSIVE

Show evidence (2 references)

PMID:33417001 SUPPORT Human Clinical

"Brain MRI showed marked cerebellar atrophy in all patients."

Present in all patients of the French series, supporting VERY_FREQUENT.

PMID:32367277 SUPPORT Human Clinical

"The brain MRIs showed a marked cerebellar atrophy of the patients."

Independent confirmation in the Taiwanese SCAR16 patients.

Cognitive Decline Mental deterioration HP:0001268

Course: PROGRESSIVE

Sequelae: Mutism

Show evidence (3 references)

PMID:31619515 SUPPORT Human Clinical

"The disease spectrum of SCAR16 includes a varying age of disease onset, cognitive dysfunction, increased tendon reflex, and hypogonadism."

Places cognitive dysfunction in the recognized SCAR16 spectrum alongside the other accompanying features curated here.

PMID:32367277 SUPPORT Human Clinical

"Clinically, the three patients from the two SCAR16 families presented with cerebellar ataxia alone or in combination with cognitive impairment."

Cognitive impairment accompanied ataxia in some Taiwanese patients, whereas others had isolated ataxia.

PMID:24742043 SUPPORT INDIRECT Human Clinical

"In contrast to previous reports, STUB1-ataxia can start even above age 40 years, and neither hypogonadism nor prominent cognitive impairment are obligatory features."

The screening cohort found cognitive impairment in one of three affected subjects, demonstrating variability rather than an obligatory feature.

Hyperreflexia HP:0001347

Show evidence (3 references)

PMID:41851873 SUPPORT Human Clinical

"The age at onset was 27 years old with clinical characteristics of cerebellar ataxia and increased tendon reflex."

A genetically confirmed SCAR16 patient with increased tendon reflex alongside the ataxia.

PMID:31619515 SUPPORT Human Clinical

"hypogonadism was found in only four patients, whereas over 70% of the patients suffered from increased tendon reflex and/or cognitive dysfunction"

The combined increased-reflex and/or cognitive-dysfunction statistic cannot establish the marginal frequency of hyperreflexia.

PMID:31619515 SUPPORT Human Clinical

"cognitive dysfunction, increased tendon reflex, and ancestry were able to predict 54% of the variation in ataxia severity"

A model fitted to published clinical reports explained 54% of SARA-score variation. Some SARA scores were imputed; ancestry may be confounded by care and environmental differences. This is a cohort association, not a validated individual prognostic tool.

Peripheral Neuropathy HP:0009830

Show evidence (2 references)

PMID:24742043 SUPPORT Human Clinical

"electrophysiological evidence of sensory axonal peripheral neuropathy."

Direct peripheral-neuropathy evidence in subject 91078; no population frequency is inferred.

PMID:32342324 SUPPORT Human Clinical

"SCAR16 is characterized by early onset spastic ataxia and a wide disease spectrum, including cognitive dysfunction, hyperkinetic disorders, epilepsy, peripheral neuropathy, and hypogonadism."

The review includes peripheral neuropathy in the SCAR16 spectrum without providing a frequency estimate.

Tremor HP:0001337

Show evidence (1 reference)

PMID:34070858 SUPPORT Other

"head and hand tremor, hyperreflexia, cognitive decline, and, occasionally, hypogonadism"

This background summary describes head and hand tremor in SCAR16; it is not a measured frequency in the functional study.

Seizures HP:0001250

Show evidence (3 references)

PMID:25258038 SUPPORT Human Clinical

"She was born prematurely and had epilepsy (generalized)"

The p.Asn65Ser sister had generalized epilepsy from infancy; the subsequent narrative reports no further seizures after early childhood.

PMID:42080998 SUPPORT Human Clinical

"Seizures were seen only in STUB1 variants."

Seizures occurred only in STUB1 cases within this reviewed Gordon Holmes sample; this does not prove exclusivity or estimate frequency in unselected SCAR16.

PMID:28193273 SUPPORT Human Clinical

"Epilepsy GTCS in early childhood GTCS (onset 35y) GTCS? (onset 42y)"

Table 2 documents generalized tonic-clonic seizures in two patients and marks the third history as GTCS?, indicating uncertainty. The abstract bundles epilepsy with the three-patient phenotype and should not be read as three confirmed cases.

Myoclonus HP:0001336

Show evidence (2 references)

url:https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf SUPPORT Human Clinical

"ataxia, spasticity, myoclonus, and cognitive deterioration"

Bettencourt 2015 (PMID:25592071), recovered full text: Direct observation in the recessive Spanish family.

PMID:24742043 SUPPORT Human Clinical

"Subject 91078 showed myoclonic jerks in the face and the left arm."

A separate p.Met240Thr patient had myoclonus; cortical localization remained a hypothesis.

Chorea HP:0002072

Show evidence (2 references)

url:https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf SUPPORT Human Clinical

"She later presented with cognitive impairment that progressed to dementia, mild generalized choreatric movements"

Bettencourt 2015 (PMID:25592071), recovered full text: Direct observation in the recessive Spanish family.

PMID:28193273 SUPPORT Human Clinical

"Extrapyramidal hyperkinetic movement disorders included choreo-athetotic movements in 2/3 subjects and dystonia in 1/3 subjects."

The full clinical results assign the choreoathetotic movements to the two affected siblings in family 2.

Delayed Gross Motor Development HP:0002194

Show evidence (1 reference)

PMID:25258038 SUPPORT Human Clinical

"Motor development has been slow."

The younger sister had delayed walking and slow acquisition of motor abilities; the full clinical narrative also documents delayed walking in the index brother.

Thin Corpus Callosum HP:0033725

Show evidence (1 reference)

PMID:25258038 SUPPORT Human Clinical

"a distinct thinning of the anterior part of the corpus callosum"

The discussion documents thinning but explicitly leaves progression and mutation specificity unresolved.

Arm Dystonia HP:0031960

Show evidence (1 reference)

PMID:28193273 SUPPORT Human Clinical

"Hyperkinetic movements (dystonia/athetosis) focal dystonia upper limb"

Table 2 identifies focal arm dystonia in family 1, establishing a direct recessive-case observation.

Mutism HP:0002300

Show evidence (1 reference)

PMID:28193273 SUPPORT Human Clinical

"leading to mutism in 2/3 cases before the age of 40."

The clinical narrative describes acquired loss of speech in two previously verbal patients.

Constitutional 1

Urge Incontinence Urinary incontinence HP:0000020

Show evidence (1 reference)

PMID:28193273 SUPPORT Human Clinical

"Urge incontinence + + + (40y) Parkinsonism hypomimia - -"

The urge-incontinence row contains positive entries for all three patients. The following parkinsonism row is retained only for quote context and is not generalized across the cases.

🧬

Genetic Associations

STUB1 variants associated with recessive ataxia

Gene: STUB1 hgnc:11427 relationship_type: CAUSATIVE

Show evidence (5 references)

PMID:24312598 SUPPORT Human Clinical

"Using Sanger sequencing, we also identified two compound heterozygous mutations"

Compound heterozygous STUB1 alleles in additional kindreds establish the biallelic requirement beyond the homozygous index family.

PMID:28396517 SUPPORT In Vitro

"six previously reported pathogenic STUB1 variants (E28K, N65S, K145Q, M211I, S236T, and T246M) were expressed as recombinant proteins"

Names the recurrent SCAR16 allele set that spans the three CHIP domains.

PMID:34070858 SUPPORT In Vitro

"These studies revealed that dominantly and recessively inherited STUB1 variants showed similar biochemical defects, including impaired ubiquitin ligase activity and altered oligomerization properties of the CHIP."

Similar in vitro defects do not distinguish dominant from recessive inheritance or establish disease penetrance in a heterozygous relative.

+ 2 more references

Variants (22)

STUB1 c.633G>A (p.Met211Ile)

single nucleotide variant

Variant detail: missense

Missense allele reported in trans with p.Glu238Ter in two affected siblings. The primary report found segregation and decreased CHIP abundance in mutant-expression cells and patient fibroblasts.

Show evidence (1 reference)

url:https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf SUPPORT Human Clinical

"compound heterozygous variants in STUB1 gene (c.633G >A, p.Met211Ile and c.712G>T, p.Glu238Ter)"

Bettencourt 2015 (PMID:25592071), recovered full text: The report identifies these two segregating alleles in the recessive family. No contemporary ACMG class is assigned here.

STUB1 c.712G>T (p.Glu238Ter)

single nucleotide variant

Variant detail: nonsense

Premature stop allele reported in trans with p.Met211Ile in the same family. Truncation and/or nonsense-mediated decay were proposed; patient RNA decay was not demonstrated in the report.

Show evidence (1 reference)

url:https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf SUPPORT Human Clinical

"compound heterozygous variants in STUB1 gene (c.633G >A, p.Met211Ile and c.712G>T, p.Glu238Ter)"

Bettencourt 2015 (PMID:25592071), recovered full text: The report identifies these two segregating alleles in the recessive family. No contemporary ACMG class is assigned here.

STUB1 p.Glu28Lys

single nucleotide variant

Variant detail: missense

TPR-domain disease-associated allele. Recombinant Hsc70- and self-ubiquitination were similar to wild type in 2017, with altered proteolytic susceptibility and oligomer distribution.

Show evidence (2 references)

PMID:28396517 SUPPORT In Vitro

"six previously reported pathogenic STUB1 variants (E28K, N65S, K145Q, M211I, S236T, and T246M)"

Names the disease-associated variant in the 2017 functional study; the description preserves its assay-specific behavior.

PMID:25258038 SUPPORT Human Clinical

"a missense change (c.82G > A, p.Glu28Lys) which was inherited in trans with a nonsense mutation (c.430A > T, p.Lys144Ter)"

The original family confirms the allele in trans with a truncating variant.

STUB1 p.Asn65Ser

single nucleotide variant

Variant detail: missense

TPR-domain disease-associated allele with impaired Hsc70 ubiquitination but preserved self-ubiquitination, increased dimerization and resistance to limited proteolysis in 2017.

Show evidence (2 references)

PMID:28396517 SUPPORT In Vitro

"six previously reported pathogenic STUB1 variants (E28K, N65S, K145Q, M211I, S236T, and T246M)"

Names the disease-associated variant in the 2017 functional study; the description preserves its assay-specific behavior.

PMID:25258038 SUPPORT Human Clinical

"a homozygous missense variant (c.194A > G, p.Asn65Ser) that segregated in three affected siblings"

Clinical segregation in the original family, distinct from recombinant functional evidence.

STUB1 p.Lys145Gln

single nucleotide variant

Variant detail: missense

Disease-associated allele with wild-type-like ubiquitination in the 2017 recombinant assays and altered protein structural properties; cellular and other-substrate effects require separate evidence.

Show evidence (3 references)

PMID:28396517 SUPPORT In Vitro

"six previously reported pathogenic STUB1 variants (E28K, N65S, K145Q, M211I, S236T, and T246M)"

Names the disease-associated variant in the 2017 functional study; the description preserves its assay-specific behavior.

PMID:28193273 SUPPORT Human Clinical

"two affected siblings (II.1 and II.4) both carried the mutations p.Lys145Gln and p.Pro243Leu."

Clinical segregation with a second allele provides evidence separate from recombinant protein assays.

PMID:41851873 SUPPORT Human Clinical

"her mother was heterozygous for the c.433 A > C variant."

The 2026 patient carried maternal p.Lys145Gln in trans with paternal p.Gln118Ter.

STUB1 p.Ser236Thr

single nucleotide variant

Variant detail: missense

Disease-associated allele with wild-type-like Hsc70- and self-ubiquitination in 2017 but altered structural stability. The 2013 HEK293 NR2A-degradation assay showed a defect, illustrating substrate- and context-dependent functional results.

Show evidence (2 references)

PMID:28396517 SUPPORT In Vitro

"six previously reported pathogenic STUB1 variants (E28K, N65S, K145Q, M211I, S236T, and T246M)"

Names the disease-associated variant in the 2017 functional study; the description preserves its assay-specific behavior.

PMID:24312598 SUPPORT Human Clinical

"c.621CG (p.Y207X) and c. 707GC (p. S236T)"

The discovery report pairs p.Ser236Thr with p.Tyr207Ter in family 3.

STUB1 p.Thr246Met

single nucleotide variant

Variant detail: missense

U-box disease allele associated with ataxia and hypogonadism in a homozygous family. Recombinant experiments show absent Hsc70- and self-ubiquitination and prominent higher-order oligomerization.

Show evidence (1 reference)

PMID:28396517 SUPPORT In Vitro

"six previously reported pathogenic STUB1 variants (E28K, N65S, K145Q, M211I, S236T, and T246M)"

Names the disease-associated variant in the 2017 functional study; the description preserves its assay-specific behavior.

STUB1 c.430A>T (p.Lys144Ter)

single nucleotide variant

Variant detail: nonsense

Truncating allele confirmed in trans with p.Glu28Lys in a woman with ataxia and hypogonadotropic hypogonadism. The mutant transcript and truncated protein were not detected in patient material, consistent with nonsense-mediated decay; the study did not directly inhibit the decay pathway to establish that mechanism. A 2026 coding-sequence overexpression experiment produced truncated p.Lys144Ter protein; that construct result does not refute the original patient-RNA observation.

Show evidence (2 references)

PMID:25258038 SUPPORT Human Clinical

"a missense change (c.82G > A, p.Glu28Lys) which was inherited in trans with a nonsense mutation (c.430A > T, p.Lys144Ter)"

The original patient report establishes the compound-heterozygous pair.

PMID:41851873 SUPPORT In Vitro

"the p.(Gln118*) and p.(Lys144*) variants generated truncated proteins"

Truncated protein was observed after expression-plasmid transfection, not measured in patient tissue.

STUB1 c.355C>T (p.Arg119Ter)

single nucleotide variant

Variant detail: nonsense

Reported in trans with p.Ile294Phe in a patient with ataxia, severe dementia, pyramidal disease and hypogonadism. Nonsense-mediated decay was predicted rather than directly demonstrated.

Show evidence (1 reference)

PMID:28193273 SUPPORT Human Clinical

"one affected individual (II.1) carried the compound heterozygeous mutations p.Arg119* and p.Ile294Phe."

The original family study confirms phase by parental testing and describes the associated recessive phenotype.

STUB1 c.880A>T (p.Ile294Phe)

single nucleotide variant

Variant detail: missense

U-box missense variant confirmed in trans with p.Arg119Ter. The 2017 primary report specifies phenylalanine at residue 294.

Show evidence (1 reference)

PMID:28193273 SUPPORT Human Clinical

"one affected individual (II.1) carried the compound heterozygeous mutations p.Arg119* and p.Ile294Phe."

The original family study confirms phase by parental testing and describes the associated recessive phenotype.

STUB1 c.728C>T (p.Pro243Leu)

single nucleotide variant

Variant detail: missense

U-box variant confirmed in trans with p.Lys145Gln in two siblings with ataxia, severe cognitive decline, spasticity and choreoathetosis.

Show evidence (1 reference)

PMID:28193273 SUPPORT Human Clinical

"two affected siblings (II.1 and II.4) both carried the mutations p.Lys145Gln and p.Pro243Leu."

The original family study confirms phase by parental testing and describes the associated recessive phenotype.

STUB1 NM_005861.2:c.612+11C>G Uncertain Significance

single nucleotide variant

Variant detail: intronic variant

Genomic context: intron

Maternally inherited homozygous intronic variant in a patient with Gordon Holmes features and chromosome-16 regions of absent heterozygosity consistent with maternal uniparental isodisomy. The 2024 online report classified the variant as uncertain despite considering the presentation diagnostic. SpliceAI and MaxEntScan predicted donor-site gain; no patient RNA or functional splice assay was reported. The case was investigated through the observational HSP Genomic Sequencing Initiative (NCT05354622); study ascertainment does not establish this variant as causal.

Show evidence (2 references)

url:https://www.def-lab.org/wp-content/uploads/2024/12/2024-Agianda-MDCP.pdf SUPPORT Human Clinical

"This variant was classi ﬁed as a variant of uncertain signi ﬁcance"

Agianda et al. (PMID:39728009), author-hosted full text: The original authors explicitly retain uncertain significance; the phenotype does not replace molecular validation of splicing.

url:https://www.def-lab.org/wp-content/uploads/2024/12/2024-Agianda-MDCP.pdf SUPPORT Human Clinical

"through the HSP Genomic Sequencing Initiative (NCT05354622)"

Agianda et al. (PMID:39728009), full text: The reported UPD/VUS case was identified through this observational study.

STUB1 NM_005861.4:c.352C>T (p.Gln118Ter) Pathogenic

single nucleotide variant

Variant detail: nonsense

Paternally inherited truncating allele in trans with maternal p.Lys145Gln in a woman with slowly progressive ataxia beginning at age 27. Classified as pathogenic in the 2026 report. Overexpression constructs produced truncated protein and reduced Hsc70 polyubiquitination; expression-vector RNA findings do not establish escape from nonsense-mediated decay in patient tissue.

Show evidence (1 reference)

PMID:41851873 SUPPORT Human Clinical

"the c.352 C > T, p.(Gln118*) variant of STUB1 was classified as pathogenic"

The 2026 authors classified this allele as pathogenic using their clinical, segregation and functional evidence.

STUB1 c.721C>T (p.Arg241Trp)

single nucleotide variant

Variant detail: missense

Reported in trans with p.Lys145Gln in a Taiwanese SCAR16 family.

Show evidence (1 reference)

PMID:32367277 SUPPORT Human Clinical

"Among them, STUB1 p.R241W and p.C232G were novel mutations."

The primary clinical abstract reports the two phased allele pairs; no contemporary ACMG classification is inferred.

STUB1 c.694T>G (p.Cys232Gly)

single nucleotide variant

Variant detail: missense

Reported in trans with p.Lys145Gln in a second Taiwanese SCAR16 family.

Show evidence (1 reference)

PMID:32367277 SUPPORT Human Clinical

"Among them, STUB1 p.R241W and p.C232G were novel mutations."

The primary clinical abstract reports the two phased allele pairs; no contemporary ACMG classification is inferred.

STUB1 p.Leu165Phe

single nucleotide variant

Variant detail: missense

Homozygous founding allele in four affected siblings; their parents and an unaffected sibling were heterozygous.

Show evidence (1 reference)

PMID:24312598 SUPPORT Human Clinical

"the patients (II:1, 2, 3 and 5) were homozygous at c.493CT (p.L165F) of CHIP"

The original clinical and segregation study reports this allele; no contemporary ACMG classification is inferred.

STUB1 p.Asn130Ile

single nucleotide variant

Variant detail: missense

Reported in trans with p.Trp147Cys in the second family of the 2013 discovery study.

Show evidence (1 reference)

PMID:24312598 SUPPORT Human Clinical

"c.389AT (p.N130I) and c.441GT (p.W147C)"

The original clinical and segregation study reports this allele; no contemporary ACMG classification is inferred.

STUB1 p.Trp147Cys

single nucleotide variant

Variant detail: missense

Reported in trans with p.Asn130Ile in the second discovery family.

Show evidence (1 reference)

PMID:24312598 SUPPORT Human Clinical

"c.389AT (p.N130I) and c.441GT (p.W147C)"

The original clinical and segregation study reports this allele; no contemporary ACMG classification is inferred.

STUB1 p.Tyr207Ter

single nucleotide variant

Variant detail: nonsense

Reported in trans with p.Ser236Thr in the third discovery family; the truncation removes the U-box domain.

Show evidence (1 reference)

PMID:24312598 SUPPORT Human Clinical

"(p.Y207X) mutation encodes a truncated protein without a U-box domain"

The original clinical and segregation study reports this allele; no contemporary ACMG classification is inferred.

STUB1 p.Leu231Val

single nucleotide variant

Variant detail: missense

Homozygous allele in Roux et al. 2020 family AAR-030 with Gordon Holmes features. Heterozygous transmitting relatives had no obvious ataxic or cognitive impairment at their reported examinations. A second homozygous ATM p.Glu299Gly VUS was not established as causal.

Show evidence (1 reference)

PMID:32713943 SUPPORT Human Clinical

"the homozygous p.L231V STUB1 variant explains the phenotype of ataxia with hypogonadism"

Table 1 and the recessive subset of Table 2 identify the allele and family. No modern ACMG class or functional assay is inferred.

STUB1 p.Ala120Val

single nucleotide variant

Variant detail: missense

Reported with p.Met211Thr as a compound-heterozygous pair in family SAL-399-729 in the 2020 series; these biallelic cases must be distinguished from the predominantly heterozygous cohort.

Show evidence (1 reference)

PMID:32713943 SUPPORT Human Clinical

"SAL-399–729 – g.681438 C>T c.359 C>T p.A120V c Missense"

Table 1 and the recessive subset of Table 2 identify the allele and family. No modern ACMG class or functional assay is inferred.

STUB1 p.Met211Thr

single nucleotide variant

Variant detail: missense

Reported with p.Ala120Val in the biallelic family SAL-399-729. This substitution differs from the p.Met211Ile allele in the 2015 autopsy family.

Show evidence (1 reference)

PMID:32713943 SUPPORT Human Clinical

"SAL-399–729 rs1481222863 g.682039 T>C c.632 T>C p.M211T c Missense"

Table 1 and the recessive subset of Table 2 identify the allele and family. No modern ACMG class or functional assay is inferred.

💊

Medical Actions

Supportive and Symptomatic Care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Other

Management is multidisciplinary symptomatic care for ataxia, dysarthria, dysphagia, pyramidal signs and, where present, endocrine and seizure manifestations. No SCAR16-specific disease-modifying intervention was identified in the September 2026 trial search. Cellular and animal therapeutic candidates remain preclinical.

Show evidence (2 references)

PMID:33200713 SUPPORT Other

"These diseases are all incurable at present, with no available treatments to modify the neurodegenerative process or provide neuroprotection."

A CHIP-focused review's framing statement about the neurodegenerative diseases it covers, which include the inherited cerebellar ataxias. It supports the absence of disease-modifying therapy at the class level rather than reporting a SCAR16-specific treatment trial; no such trial was found.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/ SUPPORT Other

"The goals of supportive care are to maximize function and reduce complications."

General hereditary-ataxia guidance, extrapolated to SCAR16: Supports multidisciplinary supportive management; this is not a SCAR16-specific efficacy study.

Physical Therapy and Gait Rehabilitation

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Balance exercises, gait training and muscle strengthening, with adaptive mobility devices and home fall-prevention measures. Recommendations are extrapolated from general hereditary-ataxia care.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/ SUPPORT Other

"PT (balance exercises, gait training, muscle strengthening) to maintain mobility"

General hereditary-ataxia guidance, extrapolated to SCAR16: Identifies the rehabilitation components and intended functional goal.

Speech and Language Therapy

Action: speech and language therapy Ontology label: Speech Language Therapy NCIT:C159273

Platform: Behavioral / lifestyle

Speech-language assessment and therapy for dysarthria, with alternative communication methods when needed. Swallowing and feeding management is addressed separately. This recommendation is extrapolated from general hereditary-ataxia care.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/ SUPPORT Other

"Consider alternative communication methods as needed"

General hereditary-ataxia guidance, extrapolated to SCAR16: The dysarthria row recommends speech-language therapy and communication aids.

Occupational Therapy

Action: occupational therapy Ontology label: Occupational Therapy NCIT:C121351

Platform: Behavioral / lifestyle

Adaptive strategies and equipment to preserve independence in daily activities as limb ataxia progresses.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/ SUPPORT Other

"supportive care by a multidisciplinary team of specialists including neurologists, occupational therapists, physical therapists"

General hereditary-ataxia guidance, extrapolated to SCAR16: Supports occupational therapy and adaptive strategies for daily activities.

Sex Hormone Replacement Therapy

Action: sex hormone replacement therapy Ontology label: Hormone Replacement Therapy NCIT:C15599

Agent: estrogen preparation (unspecified) progestin preparation (unspecified)

Platform: Small molecule

Individualized endocrine replacement addresses sex-steroid deficiency in patients with hypogonadotropic hypogonadism. In the original homozygous p.Thr246Met sisters, estrogen/progestin supplementation induced menstrual bleeding after three weeks. This endocrine response does not establish neurological benefit or restoration of spontaneous gonadotropin function.

Mechanism Target:

Hypothalamic-Pituitary Gonadotropin Deficiency — Replaces the sex steroids that the deficient gonadotropin drive fails to elicit, without acting on the CHIP defect upstream.

Trehalose (Preclinical Patient-Fibroblast Candidate)

Action: Pharmacotherapy NCIT:C15986

Agent: trehalose CHEBI:27082

Platform: Small molecule

Trehalose reduced epoxomicin-associated cell injury and oxidative-stress readouts and increased autophagy-associated readouts in fibroblasts from one SCAR16 patient with p.Met211Ile/p.Glu238Ter variants. The study used three control donors and patient culture pseudoreplicates; patient-versus-control statistical comparisons were not valid. Increased CHIP abundance did not establish restored mutant CHIP function, and the authors did not attribute protection to that increase. This is a cell-culture therapeutic lead, not evidence of clinical efficacy.

Mechanism Target:

Failure of Chaperone-Assisted Protein Quality Control — Candidate enhancement of alternative protein-clearance pathways, with increased autophagy readouts and reduced stress-associated injury in patient fibroblasts. Restoration of CHIP ligase activity or thermostability was not demonstrated.

Show evidence (1 reference)

PMID:25259530 SUPPORT In Vitro

"Induction of autophagy by trehalose improved UPS malfunction by epoxomicin as well as viability problems, autophagy failure and ROS generation effects because of CHIP mutations."

The primary study interprets the cellular protection through autophagy and proteostasis; this is not a demonstrated rescue of CHIP catalytic function.

Show evidence (2 references)

PMID:25259530 SUPPORT In Vitro

"Although this is an individual case based on only one patient and the statistical comparisons are not valid between controls and patient"

The authors explicitly limit the inference from this single patient and culture pseudoreplicates.

PMID:25259530 REFUTE In Vitro

"We do not believe that the improvement of CHIP mutant fibroblasts is related to this elevation of CHIP levels"

The authors reject increased CHIP abundance as their explanation for protection. The treatment is therefore not classified as a demonstrated CHIP stabilizer.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Counseling should establish the familial variants, their phase and parental origin. When both parents are heterozygous carriers of the recessive familial alleles, each pregnancy has a 25% chance of an affected child. This recurrence figure does not apply automatically to a uniparental-isodisomy case. Dominant STUB1 disease complicates interpretation of heterozygous relatives; variant-specific segregation and clinical evidence are needed.

Show evidence (2 references)

PMID:34070858 SUPPORT In Vitro

"Our findings expand the molecular understanding of SCA48 but also mean that assumptions concerning unaffected carriers of recessive STUB1 variants in SCAR16 families must be re-evaluated."

Supports the counseling caveat that SCAR16 heterozygotes cannot be assumed unaffected.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/ SUPPORT Other

"each sib of an affected individual has at conception a 25% chance of being affected"

General hereditary-ataxia guidance, extrapolated to SCAR16: This figure is conditional on both parents being heterozygous for familial pathogenic variants. It does not override the STUB1-specific dominant-allele and uniparental-disomy caveats.

Swallowing and Nutritional Support

Platform: Other

Assess nutrition and aspiration risk when choking or dysphagia develops. Modify food consistency based on swallowing assessment and consider enteral feeding for severe dysfunction. General hereditary-ataxia guidance is supported by reported tube-feeding needs in SCAR16.

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/ SUPPORT Other

"For those w/frequent choking or severe dysphagia, assess nutritional status"

General hereditary-ataxia guidance, extrapolated to SCAR16: Supports assessment and feeding-team involvement.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/ SUPPORT Other

"Video esophagram may help define best consistency."

General hereditary-ataxia guidance, extrapolated to SCAR16: Supports food-consistency adjustment.

PMID:28193273 SUPPORT Human Clinical

"necessitating gastric tube feeding in both subjects from family 2 at the age of 36 and 43, respectively."

Two affected siblings required tube feeding for severe dysphagia.

Symptomatic Treatment of Spasticity

Action: Pharmacotherapy NCIT:C15986

Agent: baclofen CHEBI:2972 tizanidine CHEBI:63629 dantrolene CHEBI:4317

Platform: Small molecule

Individualized antispasticity treatment may include baclofen, tizanidine or dantrolene. This is extrapolated hereditary-ataxia management; SCAR16-specific efficacy has not been demonstrated.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/ SUPPORT Other

"Baclofen, tizanidine, or dantrolene may relieve muscle spasms"

General hereditary-ataxia guidance, extrapolated to SCAR16: Lists symptomatic options for upper-motor-neuron involvement.

Cognitive and Psychiatric Support

Platform: Other

Assess cognitive and emotional difficulties, with neuropsychological rehabilitation, psychotherapy and standard treatment for psychiatric symptoms as indicated. This is extrapolated general hereditary-ataxia care.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/ SUPPORT Other

"Standard treatment for psychiatric manifestations"

General hereditary-ataxia guidance, extrapolated to SCAR16: Supports treatment when psychiatric manifestations occur, without asserting their frequency in SCAR16.

Longitudinal Neurologic and Functional Surveillance

Platform: Other

General hereditary-ataxia guidance recommends annual neurologic and rehabilitation review, including a standardized ataxia scale and assessment of mobility and falls. Reassess speech, swallowing, nutrition and cognition with symptom progression, and family support needs at each visit. This is a general-care framework, not a SCAR16-specific surveillance protocol.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/ SUPPORT Other

"Monitor ataxia progression w/standardized scale (SARA)."

General hereditary-ataxia guidance, extrapolated to SCAR16: Table 7 recommends annual neurologic and functional review, more often for acute exacerbation.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/ SUPPORT Other

"Assess aspiration risk & feeding methods."

General hereditary-ataxia guidance, extrapolated to SCAR16: Swallowing surveillance follows symptom progression.

BAY 73-6691 (Preclinical PDE9A Inhibition)

Action: Pharmacotherapy NCIT:C15986

Agent: BAY 73-6691 CHEBI:231440

Platform: Small molecule

The PDE9A inhibitor BAY 73-6691 improved motor coordination, gait, water-maze performance, Purkinje-cell density and mitochondrial injury readouts in homozygous T246M male rats. The initial study treated animals from 5.5 months of age for 15 days and assessed them around six months. This is a preclinical research compound; clinical efficacy, safety and a human regimen are not established.

Mechanism Target:

PDE9A Accumulation — Inhibits PDE9A enzymatic activity and is associated with restored cGMP/CHIP signaling and lower PDE9A abundance in the rat model.

Show evidence (2 references)

PMID:39806097 SUPPORT Model Organism

"the levels of CHIP, cGMP, PKG1 and PKG2 were diminished in the Hom group, and the PDE9A level was increased"

Rat cerebellar and hippocampal measurements include cGMP ELISA and protein assays. These establish the model state; they are not patient biomarker measurements.

PMID:39806097 SUPPORT Model Organism

"After the inhibition of PDE9A with Bay 73-6691, a conspicuous increase in CHIP S20 phosphorylation was detected"

The phospho-specific antibody detects the rodent S20 site, corresponding to human S19. Inhibitor and AAV interventions support the feedback model.

Show evidence (2 references)

PMID:39806097 SUPPORT Model Organism

"Hom(6M+) rats treated with Bay 73-6691 performed similarly to age-matched wild-type and presymptomatic Hom(6M-) rats, which was consistent with improved motor function"

In homozygous mutant male rats, PDE9A inhibition improved rotarod and beam performance; no human treatment was studied.

PMID:39806097 SUPPORT Other

"the PDE9A inhibitor Bay 73-6691 is currently in the early stages of preclinical research"

The authors explicitly limit translational readiness.

AAV-Mediated CHIP Supplementation (Preclinical)

Action: Gene Therapy NCIT:C15238

Platform: Gene therapy

Intravenous delivery of a brain-penetrant AAV-CHIP construct to homozygous T246M male rats increased brain CHIP and improved motor, memory, Purkinje-cell density and mitochondrial readouts at approximately six weeks after injection. This is experimental gene supplementation in one allele model; the study does not establish benefit or safety in people. Higher endpoint cell density does not demonstrate regeneration of previously lost neurons.

Mechanism Target:

Reduced CHIP Protein Abundance — Supplies additional wild-type CHIP in the mutant rat; this is gene addition rather than correction of the endogenous allele.

Show evidence (1 reference)

PMID:39806097 SUPPORT Model Organism

"the virus efficiently penetrated the brain tissue of homozygous mutant rats, increasing CHIP protein levels"

The brain-penetrant AAV construct increased CHIP abundance in mutant rat brain.

Show evidence (2 references)

PMID:39806097 SUPPORT Model Organism

"behavioural observations revealed improved balance, coordination and gait in the homozygous mutant rats"

AAV-mediated CHIP supplementation improved motor and memory readouts in mutant rats, with an empty-vector cohort in the genetic-intervention experiment.

PMID:39806097 SUPPORT Model Organism

"Treatment with Bay 73-6691 or AAV-CHIP resulted in a reduction in scores, indicating mitigated mitochondrial damage and morphological improvements in the mutated rats"

4-Aminopyridine (Uncontrolled UPD/VUS Case Report)

Action: Pharmacotherapy NCIT:C15986

Agent: 4-aminopyridine CHEBI:34385

Platform: Small molecule

One patient with maternal chromosome-16 isodisomy and a homozygous STUB1 c.612+11C>G variant of uncertain significance received 4-aminopyridine after ataxia worsened at age 18. Her BARS score was stable at age 20. The report does not demonstrate improvement, a causal treatment effect or molecularly confirmed SCAR16; it is an uncontrolled therapeutic observation.

Show evidence (1 reference)

url:https://www.def-lab.org/wp-content/uploads/2024/12/2024-Agianda-MDCP.pdf SUPPORT Human Clinical

"4-aminopyridine was initiated, and follow-up at age 20 showed a stable BARS score"

Agianda et al. (PMID:39728009), full text: Stability after treatment in a single case cannot establish efficacy. The source classifies the intronic variant as a VUS without RNA confirmation.

Antiseizure Treatment (Reported Levetiracetam Response)

Action: Pharmacotherapy NCIT:C15986

Agent: levetiracetam CHEBI:6437

Platform: Small molecule

Treat clinically diagnosed epilepsy as indicated. Levetiracetam controlled generalized tonic-clonic seizures in the reported maternal-UPD case carrying the STUB1 intronic VUS. This individual response does not establish a preferred antiseizure drug for genetically confirmed SCAR16.

Show evidence (1 reference)

url:https://www.def-lab.org/wp-content/uploads/2024/12/2024-Agianda-MDCP.pdf SUPPORT Human Clinical

"tonic–clonic seizures that responded to levetiracetam."

Agianda et al. (PMID:39728009), full text: The case documents symptomatic seizure control; disease attribution remains limited by the unresolved variant classification.

🔬

Diagnosis

Biallelic STUB1 sequencing with supportive MRI

Diagnosis combines a compatible phenotype with biallelic pathogenic STUB1 variants. Sequencing is needed because repeat-expansion testing alone does not assess conventional STUB1 variants. Parental segregation can establish phase. Functional assays can support variant interpretation, but preserved activity in one assay does not exclude pathogenicity. Cerebellar atrophy supports the clinical assessment but does not independently distinguish SCAR16 from SCA48. A single heterozygous variant requires assessment for a dominant mechanism; zygosity alone is insufficient. The published maternal-isodisomy case involved a VUS with a predicted, unconfirmed splice effect.

Show evidence (5 references)

PMID:41851873 SUPPORT Human Clinical

"The whole-exome sequencing combined with long-range flanking polymerase chain reaction (PCR) were performed in a Chinese SCAR16 patient."

The abstract names the testing methods, but parental segregation in the full report establishes phase; the long-range PCR addressed repeat-expansion differentials.

PMID:41851873 SUPPORT In Vitro

"we used quantitative real-time PCR and western blot analysis to investigate the function of variant in STUB1 in cultured cells"

The functional work-up used to classify a novel STUB1 variant as pathogenic rather than uncertain.

PMID:32367277 SUPPORT Human Clinical

"The brain MRIs showed a marked cerebellar atrophy of the patients."

Cerebellar atrophy on MRI is the supportive imaging finding that accompanies the genetic diagnosis.

+ 2 more references

📊

Prevalence

German ataxia and spastic paraplegia referral cohort

Unknown Rare

Diagnostic yield within a referral population, not a population prevalence. Three of 167 degenerative ataxia subjects carried biallelic STUB1 variants; none of 133 spastic paraplegia subjects did. Recorded as UNKNOWN measure type because a diagnostic-yield fraction is neither a prevalence nor an incidence, and no population-level estimate for SCAR16 exists in the literature reviewed.

Show evidence (2 references)

PMID:24742043 SUPPORT Human Clinical

"We identified 3 ataxia patients (3/167 = 1.8%) with 4 novel missense mutations in STUB1"

The study reports STUB1-related recessive ataxia in 3 of 167 degenerative-ataxia referrals and no STUB1 cases among 133 subjects with predominant spastic paraplegia. These are diagnostic yields in selected cohorts, not a population prevalence.

PMID:24742043 SUPPORT Human Clinical

"STUB1 is rare in subjects with predominant spastic paraplegia (0/133)"

Records the zero yield in the spastic paraplegia arm of the same screening study.

Taiwanese cerebellar ataxia families

Unknown Rare

Diagnostic yield, not a population prevalence: two SCAR16 pedigrees among 512 Taiwanese families screened for cerebellar ataxia.

Show evidence (1 reference)

PMID:32367277 SUPPORT Human Clinical

"SCAR16 seems to be an uncommon ataxic syndrome, accounting for 0.4% (2/512) of our cohort with cerebellar ataxia."

Source of the 0.4% yield in the Taiwanese ataxia cohort.

German and Belgian ataxia index cohorts

Unknown Rare

Diagnostic yield in exome-screened ataxia index subjects, not a population prevalence.

Show evidence (1 reference)

PMID:28193273 SUPPORT Human Clinical

"We identified four novel STUB1 mutations in three affected subjects from two index families (frequency 2/87 = 2.3%)."

Source of the 2.3% yield among ataxia index subjects.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Autosomal Recessive Spinocerebellar Ataxia 16:

Spinocerebellar ataxia 48 MONDO:0032526

Overlapping Features The allelic autosomal dominant disorder, caused by heterozygous variants in the same gene, curated in this knowledge base as Spinocerebellar Ataxia 48.

Distinguishing Features

Biallelic pathogenic variants support recessive SCAR16, whereas a heterozygous variant with evidence for a dominant effect can support SCA48. Variant interpretation and family segregation remain necessary.
SCA48 is adult-onset with a prominent cerebellar cognitive-affective and psychiatric syndrome, often with chorea, and shows dentate-nucleus T2 hyperintensity on MRI; SCAR16 starts earlier, with spastic-ataxic features and, in a subset, hypogonadism.
The separation is not clean. One variant has been reported causing both forms, and the two entities are described as a continuum rather than as discrete diseases.

Show evidence (2 references)

PMID:33417001 SUPPORT Human Clinical

"We also report the first pathogenic variation associated with both dominant and recessive forms of inheritance (SCAR16 and SCA48)."

One allele producing both the recessive and the dominant disorder is why the differential cannot be settled on variant identity alone.

PMID:32342324 SUPPORT Human Clinical

"SCA48 is an adult-onset syndrome characterized by ataxia and cognitive-psychiatric features, variably associated with chorea, parkinsonism, dystonia, and urinary symptoms."

The SCA48 clinical description against which SCAR16 is distinguished.

Gordon Holmes syndrome due to RNF216, OTUD4 or PNPLA6 MONDO:0008935

Overlapping Features Other genetic causes of ataxia with hypogonadism overlap clinically with STUB1 disease. Molecular testing distinguishes the etiologies.

Distinguishing Features

Clinical overlap makes molecular confirmation important.
Across published Gordon Holmes cases, RNF216 accounts for the majority and STUB1 for a small minority.
In the ascertained Gordon Holmes case review, seizures were reported only in its STUB1 subset, which also had the lowest median onset; this is not a diagnostic rule or biological exclusion for other causes.

Show evidence (2 references)

PMID:42080998 SUPPORT Human Clinical

"There was total 29 reported cases of GHS with RNF216 variants, 9 cases with PNPLA6 variants, and 5 with STUB1 variant."

Gives the relative contribution of each gene to published Gordon Holmes cases, which is what makes STUB1 the minority possibility in that presentation.

PMID:42080998 SUPPORT Human Clinical

"The median age at onset was lower and duration of illness was longer in STUB1 variants."

Source of the age-at-onset discriminator recorded in the distinguishing features.

📊

Related Datasets

Transcriptomic analysis of STUB1 knockdown in HEK293 cells under normal and heat-shock conditions geo:GSE310700

RNA-seq of HEK293 cells carrying shRNA against STUB1 versus non-targeting control, under basal conditions and after acute heat shock. This is a knockdown cell-line experiment, not SCAR16 patient material, and the submitters generated it for a study of the dominant allelic disorder SCA48. It is included for its direct perturbation of STUB1 in the heat-shock response, the axis addressed in the HUMAN_MODEL_MISMATCH discussion.

human BULK RNA SEQ

Dataset relevance triage. `just discover-datasets` returned twelve candidates and eleven were rejected. The three scored DIRECT are mouse studies of TDP2 and SNX14, matched only on the words "autosomal recessive spinocerebellar ataxia" in their summaries; they are different recessive ataxias and are the Named Entity Confusion case the curation guide warns about. The GENE_ONLY hits are STUB1 in tumour immunology, prostate cancer and epithelial NF-kB signalling, none of which bear on cerebellar degeneration. No SCAR16 patient-derived omics dataset was found in GEO.

Show evidence (1 reference)

GEO:GSE310700 SUPPORT In Vitro

"to investigate the role of the STUB1/CHIP co-chaperone/E3 ligase in the cellular heat-shock response and proteostasis"

The repository's own summary states the dataset's purpose, which is what makes it relevant to the proteostasis node here.

OMIX https://ngdc.cncb.ac.cn/omix/release/OMIX008238

Open-access OMIX008238, BioProject PRJCA033500: four downloadable expression-matrix archives for wild-type, homozygous T246M, mutant plus BAY 73-6691, and mutant plus AAV-CHIP conditions. The paper analyzes combined hippocampal and cerebellar single-cell suspensions; these are rat intervention data, not human patient samples.

rat SINGLE CELL RNA SEQ

PMID:39806097

Repository identity and open-access listing verified directly and cached September 2026. Figure 6 reports three rats per group; the methods wording is inconsistent, so no unqualified sample_count is assigned. The cell-level pathway scores do not measure autophagic flux. Raw matrices were not reanalyzed.

Show evidence (1 reference)

url:https://ngdc.cncb.ac.cn/omix/release/OMIX008238 SUPPORT Model Organism

"Single-cell transcriptome sequencing expression matrix."

The repository identifies the rat genotypes and interventions, links PRJCA033500 and the 2025 paper, and lists four matrix archives.

🧫

Experimental Models

SCAR16 patient primary fibroblasts PRIMARY_CELL_CULTURE

Primary skin fibroblasts from three SCAR16 patients tested for heat-shock response induction and recovery. The corresponding patient-derived cortical neurons show a different response.

Publication

PMID:33097556

Pathograph links

Failure of Chaperone-Assisted Protein Quality Control partially recapitulates fidelity: low observes: cellular Patient fibroblasts show impaired heat-shock response induction and recovery, a cellular readout of disturbed proteostasis.

Limitations: Fibroblast is not the disease target tissue, and the same study's patient neurons do not reproduce this defect, so the fibroblast phenotype cannot be read as the neuropathological mechanism. Fidelity is LOW for that reason, not because the measurement is unreliable.

Readouts

Heat shock response induction and recovery

Direction: DECREASED

Interpretation: Patient-cell readout of disturbed proteostasis.

Show evidence (1 reference)

PMID:33097556 SUPPORT In Vitro

"We found impaired HSR induction and recovery compared to healthy controls."

Reports the heat-shock response measurement in patient fibroblasts.

Show evidence (1 reference)

PMID:33097556 SUPPORT In Vitro

"we investigated the heat shock response (HSR) in primary fibroblasts of three SCAR16 patients"

Establishes that the model is built from SCAR16 patient material rather than from an unrelated CHIP-deficient line.

SCAR16 patient iPSC-derived cortical neurons IPSC_DERIVED_MODEL

Cortical neurons differentiated from three SCAR16 patient iPSC lines, compared with control lines and an isogenic STUB1 knockout. The day-36 neurons expressed cortical-layer markers and most closely resembled fetal neocortex at postconception week 16. They model a neuronal context but do not establish the response of mature cerebellar Purkinje cells.

Publication

PMID:33097556

Pathograph links

Failure of Chaperone-Assisted Protein Quality Control partially recapitulates fidelity: moderate observes: cellular Proteomic enrichment patterns were consistent with altered protein folding and oxidative-stress responses in patient cortical neurons. These are proteomic inferences rather than direct measurements of protein-refolding capacity or reactive oxygen species.

Limitations: Immature cortical neurons rather than mature Purkinje cells. High basal HSP70 and culture conditions may limit the heat-shock response. Patient and knockout neurons did not reproduce the fibroblast HSR defect; proteomic pathway enrichment does not itself demonstrate defective refolding or elevated reactive oxygen species.

Readouts

Proteomic enrichment of protein-folding and oxidative-stress pathways

Direction: ALTERED

Interpretation: Protein-abundance and pathway-enrichment differences support altered proteostasis responses; no direct refolding or ROS assay is represented by this readout.

Show evidence (1 reference)

PMID:33097556 SUPPORT In Vitro

"Proteomic analysis of CNs showed dysfunctional protein (re)folding and higher basal oxidative stress levels in patients."

The abstract summarizes the authors' interpretation of proteomic differences. The full-text results establish protein-abundance and enrichment patterns, not direct functional refolding or ROS measurements.

Show evidence (1 reference)

PMID:33097556 REFUTE In Vitro

"Our results question the role of impaired HSR in SCAR16 neuropathology and highlight the need for careful selection of proper cell types for modeling human diseases."

The authors question impaired neuronal HSR as the explanation for disease; the model link is limited to proteomic differences and does not establish mature Purkinje-cell behavior.

Show evidence (2 references)

PMID:33097556 SUPPORT In Vitro

"we next investigated the HSR in cortical neurons (CNs) derived from induced pluripotent stem cells of SCAR16 patients"

Establishes the neuronal model as patient-derived and as the cell type the study treats as disease-relevant.

PMID:33097556 SUPPORT In Vitro

"The better stress coping of CNs could be a result of the immaturity of the CNs"

The authors identify neuronal immaturity as a possible explanation for the apparent heat-stress resistance.

SCAR16 p.Met211Ile/p.Glu238Ter patient fibroblasts under proteasome stress PRIMARY_CELL_CULTURE

Skin fibroblasts from one affected member of a Spanish family with compound heterozygous p.Met211Ile/p.Glu238Ter STUB1 variants, studied alongside three age- and sex-matched control donors. Epoxomicin challenge and trehalose treatment interrogated cell survival, oxidative stress and protein clearance.

Publication

PMID:25259530

Pathograph links

Failure of Chaperone-Assisted Protein Quality Control partially recapitulates fidelity: low observes: cellular Patient fibroblasts showed stress-associated cell injury, protein ubiquitination and autophagy abnormalities, with improvement in several readouts after trehalose.

Limitations: One patient, non-neuronal tissue and pharmacological proteasome inhibition. Culture replicates are pseudoreplicates, not independent patients. No valid patient-versus-control statistical comparison or demonstrated clinical efficacy; improved mutant CHIP ligase function was not established.

Readouts

Epoxomicin-associated apoptosis and trehalose response

Direction: ALTERED

Interpretation: Cleaved-caspase-3 staining measures cellular injury under proteasome stress; trehalose-associated rescue does not establish a neuronal treatment effect.

Show evidence (1 reference)

PMID:25259530 SUPPORT In Vitro

"Additionally, treatment with epoxomicin produced a dose-dependent increase in the number of cleaved caspase-3 positive cells."

Direct cellular apoptosis readout under the experimental proteasome challenge.

Show evidence (1 reference)

PMID:25259530 SUPPORT In Vitro

"The patient's fibroblasts with a new form of hereditary ataxia, related to STUB1 gene (CHIP) mutations, and three age and sex-matched controls were treated with epoxomicin and trehalose."

Defines the patient-derived model and comparator donors.

Recombinant CHIP disease-variant biochemistry OTHER

E. coli-expressed wild-type and six disease-associated CHIP proteins tested for Hsc70- and self-ubiquitination, limited trypsin proteolysis, oligomerization and circular-dichroism unfolding. Several structural assays used MBP fusion proteins.

Publication

PMID:28396517

Pathograph links

Loss of CHIP E3 Ubiquitin Ligase Activity partially recapitulates fidelity: moderate observes: molecular Reproduces substrate-ubiquitination defects for N65S and T246M, while four other variants retain wild-type-like activity in these assays.

Limitations: Purified proteins and selected substrates do not reproduce neuronal protein abundance or all CHIP clients. MBP may influence folding and oligomerization.

Readouts

Hsc70 ubiquitination

Direction: ALTERED

Interpretation: The catalytic phenotype differs by allele and substrate.

Show evidence (1 reference)

PMID:28396517 SUPPORT In Vitro

"N65S and T246M displayed impaired Hsc70-ubiquitination activity for both MBP-fusion and MBP-free forms."

Direct assay result for two variants; it is not generalized to the whole panel.

Show evidence (1 reference)

PMID:28396517 SUPPORT In Vitro

"six previously reported pathogenic STUB1 variants (E28K, N65S, K145Q, M211I, S236T, and T246M) were expressed as recombinant proteins"

Defines the experimental allele panel.

STUB1 truncation constructs in SH-SY5Y and HEK293T cells CELL_LINE

Transient overexpression of wild-type, p.Gln118Ter, p.Lys144Ter and p.Lys145Gln coding-sequence constructs in SH-SY5Y cells assessed transcript and protein abundance. HEK293T cotransfection with Hsc70 and tagged ubiquitin assessed Hsc70 polyubiquitination for p.Gln118Ter and p.Lys145Gln. These are expression-construct assays, not patient-derived neurons.

Publication

PMID:41851873

Pathograph links

Loss of CHIP E3 Ubiquitin Ligase Activity partially recapitulates fidelity: moderate observes: molecular The p.Gln118Ter construct produced truncated CHIP with reduced Hsc70 polyubiquitination.

Limitations: Overexpression does not reproduce endogenous allelic dosage or establish patient-tissue transcript stability.

Show evidence (1 reference)

PMID:41851873 SUPPORT In Vitro

"this truncation mutant exhibited significantly reduced ubiquitination activity toward Hsc70"

The cellular ubiquitination assay supplies functional evidence for the truncation.

Show evidence (1 reference)

PMID:41851873 SUPPORT In Vitro

"Cells were harvested 48 h post-transfection for RNA level and protein level analysis."

The experimental methods identify the expression-plasmid system and assay timing.

CHIP-perturbed U2OS Parkin mitophagy reporter cells CELL_LINE

U2OS osteosarcoma cells with stable GFP-Parkin and inducible mitochondrial mKeima were subjected to STUB1 knockdown or CHIP overexpression and CCCP stress. Parkin recruitment, PINK1 abundance and pH-sensitive mitochondrial reporter delivery to lysosomes were measured. U2OS cells lack detectable endogenous Parkin in this system.

Publication

PMID:39117117

Pathograph links

Excess PINK1/Parkin-Mediated Mitophagy perturbs fidelity: low observes: cellular CHIP knockdown increases stress-induced mitophagy; wild-type CHIP overexpression suppresses it.

Limitations: Engineered non-neuronal cells under acute chemical stress, without a recessive patient genotype. SCA48-variant overexpression experiments in the same paper do not establish SCAR16-specific function.

Readouts

mt-Keima mitophagy-positive cells after CHIP knockdown and CCCP

Direction: INCREASED

Interpretation: Greater mitochondrial reporter exposure to the acidic lysosomal environment.

Show evidence (1 reference)

url:https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf SUPPORT INDIRECT In Vitro

"CHIP knockdown significantly increased the percentage of cells undergoing mitophagy"

Earnshaw et al. 2024 (PMID:39117117), recovered full text: Measured by flow cytometry in the engineered U2OS reporter system after CCCP.

Show evidence (1 reference)

url:https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf SUPPORT INDIRECT In Vitro

"U2OS cells are specifically reliant on the PINK1/Parkin pathway for mitophagy"

Earnshaw et al. 2024 (PMID:39117117), recovered full text: The next sentences specify the need for added Parkin, limiting the model to the engineered pathway.

Show evidence (1 reference)

url:https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf SUPPORT INDIRECT In Vitro

"U2OS cells stably expressing GFP-Parkin or both GFP-Parkin and mito-mKeima"

Earnshaw et al. 2024 (PMID:39117117), recovered full text: The methods identify the reporter cell systems.

SCAR16 AX71 and AX29 fibroblast PKA-signaling assays PRIMARY_CELL_CULTURE

Primary skin fibroblasts from two distinct SCAR16 patients compared with healthy-volunteer cells. Forskolin stimulation and H89 inhibition probe the dynamic PKA-CREB response; AX71 was assessed by immunostaining and AX29 by immunoblotting.

Publication

PMID:31189917

Pathograph links

Elevated Basal PKA-CREB Signaling partially recapitulates fidelity: moderate observes: cellular Increased basal CREB phosphorylation and blunted further induction by forskolin model defective signaling attenuation.

Limitations: Patient-derived non-neuronal cells; variant identities are not specified in this paper. The experiments do not establish human neuronal pathology, endocrine causation or treatment benefit.

Readouts

Basal CREB phosphorylation

Direction: INCREASED

Interpretation: Increased basal CREB phosphorylation and blunted further induction by forskolin model defective signaling attenuation.

Show evidence (1 reference)

PMID:31189917 SUPPORT In Vitro

"STUB1 mutations, like CHIP downregulation, increased basal levels of phosphoCREB-positive nuclei that could not be further induced by FSK."

Increased basal CREB phosphorylation and blunted further induction by forskolin model defective signaling attenuation.

Show evidence (1 reference)

PMID:31189917 SUPPORT In Vitro

"STUB1 mutations, like CHIP downregulation, increased basal levels of phosphoCREB-positive nuclei that could not be further induced by FSK."

Increased basal CREB phosphorylation and blunted further induction by forskolin model defective signaling attenuation.

Show evidence (1 reference)

PMID:31189917 SUPPORT In Vitro

"STUB1 mutations, like CHIP downregulation, increased basal levels of phosphoCREB-positive nuclei that could not be further induced by FSK."

Increased basal CREB phosphorylation and blunted further induction by forskolin model defective signaling attenuation.

SCAR16 AX71 fibroblast cilium-resorption assay PRIMARY_CELL_CULTURE

Serum-starved primary SCAR16 AX71 fibroblasts and control BJ cells were exposed to forskolin. Acetylated-tubulin staining quantified ciliation; NEK10 siRNA tested pathway dependence.

Publication

PMID:29581457

Pathograph links

Impaired cAMP-Induced Cilium Resorption partially recapitulates fidelity: moderate observes: cellular Cilia persist after forskolin in the patient-cell assay, whereas control cells undergo resorption.

Limitations: Non-neuronal model with a culture-condition-dependent effect; the paper does not establish that impaired cilium resorption causes SCAR16 symptoms. The separate medaka experiment perturbs NEK10 rather than STUB1 and is not a SCAR16 animal model.

Readouts

Forskolin-induced cilium resorption

Direction: DECREASED

Interpretation: Cilia persist after forskolin in the patient-cell assay, whereas control cells undergo resorption.

Show evidence (1 reference)

PMID:29581457 SUPPORT In Vitro

"no major effects of FSK stimulation on cilia were evident in SCAR16 fibroblasts."

Cilia persist after forskolin in the patient-cell assay, whereas control cells undergo resorption.

Show evidence (1 reference)

PMID:29581457 SUPPORT In Vitro

"no major effects of FSK stimulation on cilia were evident in SCAR16 fibroblasts."

Cilia persist after forskolin in the patient-cell assay, whereas control cells undergo resorption.

Show evidence (1 reference)

PMID:29581457 SUPPORT In Vitro

"no major effects of FSK stimulation on cilia were evident in SCAR16 fibroblasts."

Cilia persist after forskolin in the patient-cell assay, whereas control cells undergo resorption.

HEK293T CHIP-PDE9A ubiquitination and turnover assays CELL_LINE

Transfected HEK293T cells compare wild-type CHIP, T246M, engineered K30A and domain deletions, alongside PDE9A Lys186 and ubiquitin-linkage mutants. Cycloheximide, bafilomycin and bortezomib distinguish protein turnover and degradation routes. Overexpression and apoptosis assays are not patient-neuron experiments.

Publication

PMID:39806097

Pathograph links

PDE9A Accumulation perturbs fidelity: low observes: molecular Substrate-site and CHIP perturbations test the ubiquitination-dependent control of PDE9A abundance.

Limitations: Heterologous overexpression; does not establish physiological stoichiometry or human neuronal injury.

Show evidence (1 reference)

PMID:39806097 SUPPORT In Vitro

"Mutation of PDE9A at K186R disrupted CHIP-mediated ubiquitination, resulting in an increased half-life and overaccumulation of PDE9A in cells"

Substrate-site mutagenesis connects ubiquitination to PDE9A turnover. Bafilomycin and bortezomib comparisons support autophagic rather than proteasomal degradation of PDE9A in this system.

Show evidence (2 references)

PMID:39806097 SUPPORT In Vitro

"the T246M mutation corroborated the role of CHIP in PDE9A polyubiquitination"

Expression and domain-mutant experiments support impaired CHIP-dependent ubiquitination of PDE9A; the disease allele is p.Thr246Met, whereas K30A is an engineered control.

PMID:39806097 SUPPORT In Vitro

"Mutation of PDE9A at K186R disrupted CHIP-mediated ubiquitination, resulting in an increased half-life and overaccumulation of PDE9A in cells"

Substrate-site mutagenesis connects ubiquitination to PDE9A turnover. Bafilomycin and bortezomib comparisons support autophagic rather than proteasomal degradation of PDE9A in this system.

HEK293 CHIP-Fbx2 NR2A-turnover reconstitution CELL_LINE

HEK293 cells coexpressed NR2A, Fbx2 and wild-type CHIP or the five discovery alleles p.Asn130Ile, p.Trp147Cys, p.Leu165Phe, p.Tyr207Ter and p.Ser236Thr. Cycloheximide chase followed NR2A abundance. Wild-type CHIP plus Fbx2 enhanced turnover; either alone did not significantly do so.

Publication

PMID:24312598

Pathograph links

Loss of CHIP E3 Ubiquitin Ligase Activity partially recapitulates fidelity: moderate observes: molecular Disease variants failed to support the wild-type CHIP/Fbx2 effect on NR2A turnover.

Limitations: Heterologous overexpression of a selected client. This experiment does not measure NMDA currents, demonstrate neuronal excitotoxicity or prove that NR2A accumulation causes SCAR16.

Show evidence (1 reference)

PMID:24312598 SUPPORT In Vitro

"none of the ARCA-associated CHIP mutants effectively promoted the degradation of NR2A"

This is a substrate-turnover phenotype, not evidence that every mutant lacks all ubiquitin ligase activity.

Show evidence (1 reference)

PMID:24312598 SUPPORT In Vitro

"Coexpression of WT CHIP and Fbx2 significantly increased the degradation of NR2A"

The combination, rather than CHIP expression alone, enhanced turnover in the reconstructed cellular system.

Temperature-dependent CHIP missense-variant assays OTHER

Recombinant proteins were assessed for HSP70 ubiquitination, chaperone-peptide binding, free ubiquitin-chain formation, thermal stability and oligomerization; transfected HEK293 cells supplied a separate protein-abundance readout. The study compared physiological and lower assay temperatures.

Publication

PMID:29317501

Pathograph links

CHIP Structural Destabilization partially recapitulates fidelity: moderate observes: molecular Most variants showed destabilization and soluble oligomer formation; effects varied across assays and alleles.

Limitations: Purified proteins, a chaperone peptide and transient overexpression cannot establish patient neuronal abundance or a clinical therapeutic response.

Show evidence (1 reference)

PMID:29317501 SUPPORT In Vitro

The aggregate biochemical result is explicitly mutation-specific.

Show evidence (1 reference)

PMID:29317501 SUPPORT In Vitro

"most mutant proteins recovered activity when the assays were performed below the mutants' melting temperature"

The abstract supports temperature-dependent recovery of function; this is not a clinical cooling intervention.

CARP-dependent CHIP sequestration in HEK293T and N2A cells CELL_LINE

Transfection, ubiquitination, live imaging and detergent-solubility assays assess CARP effects on CHIP. K30A and H260Q are engineered controls; the disease-variant panel includes N65S, K145Q, M240T, T246M and I294F.

Publication

PMID:36853170

Pathograph links

CARP-Dependent CHIP Aggregate Formation perturbs fidelity: low observes: cellular CARP expression promotes CHIP sequestration into insoluble material.

Limitations: Overexpression systems; no patient-neuron validation or therapeutic inhibitor was tested.

Show evidence (1 reference)

PMID:36853170 SUPPORT In Vitro

"pathogenic mutants of STUB1 are more prone than the wild-type to CARP2-mediated aggregate assembly."

CARP2 modifies mutant CHIP and promotes aggregate assembly in experimental systems; human neuronal causation is untested.

Show evidence (1 reference)

PMID:36853170 SUPPORT In Vitro

"CARP2 interacts and mono-ubiquitinates STUB1."

Experimental interaction and modification of CHIP by CARP2.

🐁

Animal Models

Chip U-box truncation zebrafish

Engineered U-box truncation abolishes detectable Hsc70 ubiquitination in the recombinant assay but retains a mono-self-ubiquitination band. Early development, longevity and breeding were reported as normal. The model captures selected cellular features of CHIP deficiency rather than a patient-specific allele.

Species

Zebrafish

Genotype

Homozygous stub1 p.Thr255ValfsTer3 U-box truncation

Publication

PMID:34630034

Pathograph links

Purkinje Cell Degeneration partially recapitulates fidelity: moderate observes: cellular Purkinje-cell body counts were reduced at 6 and 24 months; cell-body area was reduced at 24 months. Dendritic organization was abnormal, with increased spine counts significant at 6 months only.

Limitations: No gross cerebellar atrophy was demonstrated through 24 months, although absolute cerebellar area was slightly smaller at that age. TUNEL analysis did not confirm cell death. Open-field locomotion and light/dark preference were not significantly altered; increased top-zone exploration in the novel tank is not a demonstrated ataxic motor deficit. The engineered truncation models only part of the human allelic spectrum.

Readouts

Purkinje cell body number and size

Direction: DECREASED

Interpretation: Purkinje-cell counts were lower at both measured ages; the reduction in cell-body area was significant only at 24 months.

Show evidence (1 reference)

PMID:34630034 SUPPORT Model Organism

"these fish displayed reduced numbers and sizes of Purkinje cell bodies and abnormal organization of Purkinje cell dendrites"

Reports the Purkinje cell measurement behind this readout.

Show evidence (1 reference)

PMID:34630034 SUPPORT Model Organism

"truncation of the Chip U-box domain leads to impaired ubiquitin ligase activity and behavioral and anatomical changes in zebrafish, illustrating the potential of zebrafish to study STUB1-mediated diseases"

The authors' own statement that the model is informative for STUB1-mediated disease.

Failure of Chaperone-Assisted Protein Quality Control partially recapitulates fidelity: moderate observes: cellular Whole-brain 26S proteasome activity was reduced at 24 months, but not at 6 months, when Purkinje-cell counts were already reduced. The timing does not establish this measured decline as the initiating cause of cell loss.

Limitations: A11 oligomer abundance and immunohistochemical NR2A, Hsp70 and ataxin-3 readouts were not significantly increased. This model does not establish generalized aggregate accumulation.

Readouts

Brain 26S proteasome activity

Direction: DECREASED

Interpretation: Whole-brain 26S proteasome activity was reduced at 24 months, but not at 6 months, when Purkinje-cell counts were already reduced. The timing does not establish this measured decline as the initiating cause of cell loss.

Show evidence (1 reference)

PMID:34630034 SUPPORT Model Organism

"Mutant fish also had decreased total 26S proteasome activity in the brain"

Reports the proteasome activity measurement.

Show evidence (2 references)

PMID:34630034 SUPPORT Model Organism

"No differences were evident in the proteasome activity of U-box–/– compared to the wild-type fish brains at a 6-month time point."

The significant reduction emerged at 24 months; earlier Purkinje-cell count abnormalities cannot be attributed directly to the measured late proteasome decline.

+ 1 more reference

Show evidence (1 reference)

PMID:34630034 SUPPORT Model Organism

"Recombinant wild-type zebrafish Chip showed ubiquitin ligase activity highly comparable to human CHIP, while the mutant Chip protein showed impaired ubiquitination of the Hsc70 substrate and Chip itself."

Establishes that the fish orthologue is functionally comparable to human CHIP and that the mutant reproduces the ligase defect, which is what makes the model informative for human STUB1 disease.

CHIP T246M knock-in mouse

Endogenous knock-in of the rodent residue corresponding to the human p.Thr246Met SCAR16 allele. The paper calls the model T246M while its mouse-locus methods identify T247M. Young mice initially learn the rotarod task, then develop progressive motor impairment, Purkinje-cell loss, reduced brain mass and cognitive readout abnormalities.

Species

Mouse

Genotype

Homozygous Stub1 p.Thr247Met knock-in, orthologous to human p.Thr246Met

Publication

PMID:30222779

Pathograph links

Purkinje Cell Degeneration partially recapitulates fidelity: moderate observes: cellular Aged knock-in mice show reduced CHIP staining and loss of calbindin-positive Purkinje cells; Figure 5H examines 52-week-old animals.

Show evidence (1 reference)

PMID:30222779 SUPPORT Model Organism

"we observed a decrease in CHIP reactivity in Purkinje cells as well as a loss in calbindin-positive cells"

The mouse-specific tissue results document the cellular lesion.

Show evidence (1 reference)

PMID:30222779 SUPPORT Model Organism

"To establish preclinical models of SCAR16, we engineered T246M at the endogenous locus in both mice and rats."

Establishes the models as purpose-built SCAR16 models carrying the patient allele at its native locus.

CHIP T246M-equivalent knock-in rat

CRISPR/Cas9-engineered Sprague Dawley rats carrying the ortholog of the human p.Thr246Met allele. The paper calls the model T246M and labels the targeting vector T247M. Rats show reduced CHIP abundance, Purkinje-cell degeneration, motor impairment, altered gait, learning deficits, lower body weight and reduced survival.

Species

Rat

Genotype

Homozygous endogenous Stub1 knock-in orthologous to human p.Thr246Met

Publication

PMID:30222779

Pathograph links

Reduced CHIP Protein Abundance partially recapitulates fidelity: moderate observes: molecular CHIP protein abundance is reduced in cerebellum, whole brain and testes and declines further with age; reduced tissue abundance is the modeled component.

Show evidence (1 reference)

PMID:30222779 SUPPORT Model Organism

"steady-state levels of CHIP-T246M expression are 40% lower"

Rat tissue measurements document reduced abundance, not direct visualization of intracellular oligomers.

Purkinje Cell Degeneration partially recapitulates fidelity: moderate observes: cellular At 32 weeks, rat cerebellar sections show reduced calbindin staining and fewer Purkinje cells.

Show evidence (1 reference)

PMID:30222779 SUPPORT Model Organism

"identified Purkinje cell degeneration, evidenced by decreased calbindin staining"

The rat-specific results and Figure 5D-E document the cerebellar cellular phenotype.

Show evidence (1 reference)

PMID:30222779 SUPPORT Model Organism

"we developed a rat model also harboring the same endogenous CHIP-T246M mutation."

The full scientific body reports rat-specific outcomes and the methods describe the CRISPR/Cas9 line.

Stub1-null mouse comparator

Comparator representing complete loss of CHIP rather than a patient missense allele. Null mice are already ataxic at weaning and fail initial rotarod learning; the knock-in mice instead show greater subsequent progression.

Species

Mouse

Genotype

Homozygous Stub1 knockout

Publication

PMID:30222779

Show evidence (1 reference)

PMID:30222779 SUPPORT Model Organism

"CHIP−/− mice were already ataxic at weaning"

The study directly contrasts the onset and progression of the null and knock-in lines.

chn-1 loss-of-function worm mitophagy reporters

Adult-day-one worms with loss of the CHIP orthologue were assessed with neuronal mitochondrial and lysosomal-delivery reporters. Increased basal neuronal mitophagy in chn-1(by155) was reduced by loss of pink-1 or pdr-1. The separate disease-analogue knock-ins in the paper model dominant SCA48 variants and are not represented as recessive patient-allele models here.

Species

Caenorhabditis elegans

Genotype

chn-1(by155) and chn-1(tm2692), with neuronal reporters; pink-1 and pdr-1 double-mutant comparisons

Publication

PMID:39117117

Pathograph links

Excess PINK1/Parkin-Mediated Mitophagy perturbs fidelity: low observes: cellular Loss of chn-1 increases basal neuronal mitochondrial delivery to lysosomes.

Limitations: Gene-level perturbation in worm neurons, without human Purkinje cells or a recessive patient allele. No causal link from this readout to human SCAR16 neurodegeneration was demonstrated.

Show evidence (1 reference)

url:https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf SUPPORT INDIRECT Model Organism

"worms, indicating that mitophagy is elevated in worms with loss of CHIP compared to WT controls"

Earnshaw et al. 2024 (PMID:39117117), recovered full text: The pH-sensitive mitochondrial reporter supports increased lysosomal delivery in the worm model.

Show evidence (1 reference)

url:https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf SUPPORT INDIRECT Model Organism

"the increase in neuronal mitophagy observed in chn-1(by155) worms is dependent on both PINK1 and Parkin."

Earnshaw et al. 2024 (PMID:39117117), recovered full text: Double-mutant comparisons establish pathway dependence in the worm loss-of-function model.

CHIP T246M rat PDE9A intervention cohorts

The 2025 follow-up used homozygous mutant male rats, wild-type littermates, BAY 73-6691 treatment and AAV-CHIP supplementation; the AAV experiment also used an empty-vector control. Outcomes included rotarod, beam traversal, gait, water maze, Purkinje-cell histology, mitochondrial electron microscopy and tissue molecular assays. Behavioral cohorts differ in endpoint age and sample size. Higher cell density at the endpoint is not a longitudinal demonstration of neuronal regeneration.

Species

Rat

Genotype

Homozygous Stub1 T246M model as designated by the study

Publication

PMID:39806097

Pathograph links

PDE9A Accumulation partially recapitulates fidelity: moderate observes: cellular Increased PDE9A protein accompanies reduced CHIP in mutant cerebellar and hippocampal tissue.

Limitations: Single homozygous rat allele model. The intervention results are preclinical and do not demonstrate the same mechanism in human patient tissue.

Readouts

PDE9A protein abundance

Direction: INCREASED

Interpretation: Increased PDE9A protein accompanies reduced CHIP in mutant cerebellar and hippocampal tissue.

Show evidence (1 reference)

PMID:39806097 SUPPORT Model Organism

"the levels of CHIP, cGMP, PKG1 and PKG2 were diminished in the Hom group, and the PDE9A level was increased"

Rat cerebellar and hippocampal measurements include cGMP ELISA and protein assays. These establish the model state; they are not patient biomarker measurements.

Show evidence (1 reference)

PMID:39806097 SUPPORT Model Organism

"the levels of CHIP, cGMP, PKG1 and PKG2 were diminished in the Hom group, and the PDE9A level was increased"

Rat cerebellar and hippocampal measurements include cGMP ELISA and protein assays. These establish the model state; they are not patient biomarker measurements.

Reduced cGMP Availability partially recapitulates fidelity: moderate observes: cellular Tissue cGMP concentrations are reduced in mutant rats and improve after treatment.

Limitations: Single homozygous rat allele model. The intervention results are preclinical and do not demonstrate the same mechanism in human patient tissue.

Readouts

Tissue cGMP concentration

Direction: DECREASED

Interpretation: Tissue cGMP concentrations are reduced in mutant rats and improve after treatment.

Show evidence (1 reference)

PMID:39806097 SUPPORT Model Organism

"the levels of CHIP, cGMP, PKG1 and PKG2 were diminished in the Hom group, and the PDE9A level was increased"

Rat cerebellar and hippocampal measurements include cGMP ELISA and protein assays. These establish the model state; they are not patient biomarker measurements.

Show evidence (1 reference)

PMID:39806097 SUPPORT Model Organism

"the levels of CHIP, cGMP, PKG1 and PKG2 were diminished in the Hom group, and the PDE9A level was increased"

Rat cerebellar and hippocampal measurements include cGMP ELISA and protein assays. These establish the model state; they are not patient biomarker measurements.

Mitochondrial Structural Injury partially recapitulates fidelity: moderate observes: cellular Mitochondrial ultrastructural injury improves after BAY 73-6691 or AAV-CHIP treatment.

Limitations: Single homozygous rat allele model. The intervention results are preclinical and do not demonstrate the same mechanism in human patient tissue.

Readouts

Mitochondrial injury score

Direction: INCREASED

Interpretation: Mitochondrial ultrastructural injury improves after BAY 73-6691 or AAV-CHIP treatment.

Show evidence (1 reference)

PMID:39806097 SUPPORT Model Organism

"Treatment with Bay 73-6691 or AAV-CHIP resulted in a reduction in scores, indicating mitigated mitochondrial damage and morphological improvements in the mutated rats"

Show evidence (1 reference)

PMID:39806097 SUPPORT Model Organism

"Treatment with Bay 73-6691 or AAV-CHIP resulted in a reduction in scores, indicating mitigated mitochondrial damage and morphological improvements in the mutated rats"

Show evidence (2 references)

PMID:39806097 SUPPORT Model Organism

"Hom(6M+) rats treated with Bay 73-6691 performed similarly to age-matched wild-type and presymptomatic Hom(6M-) rats, which was consistent with improved motor function"

In homozygous mutant male rats, PDE9A inhibition improved rotarod and beam performance; no human treatment was studied.

PMID:39806097 SUPPORT Model Organism

"behavioural observations revealed improved balance, coordination and gait in the homozygous mutant rats"

AAV-mediated CHIP supplementation improved motor and memory readouts in mutant rats, with an empty-vector cohort in the genetic-intervention experiment.

{ }

Source YAML

click to show

name: Autosomal Recessive Spinocerebellar Ataxia 16
creation_date: '2026-09-05T00:00:00Z'
category: Mendelian
description: Autosomal recessive spinocerebellar ataxia 16 (SCAR16) is a progressive cerebellar degeneration caused by biallelic pathogenic variants in STUB1, which encodes CHIP (C-terminus of HSC70-interacting protein), a dimeric co-chaperone and U-box E3 ubiquitin ligase that couples the HSP70/HSC70 chaperone machinery to the ubiquitin-proteasome system. Disease variants have allele-dependent effects on CHIP structure, stability, chaperone interactions and ubiquitination. Some retain activity in individual biochemical assays, so a universal catalytic-null mechanism does not explain the disorder. The clinical core is progressive gait and limb ataxia with dysarthria and marked cerebellar atrophy on MRI. Pyramidal tract involvement (hyperreflexia, lower-limb spasticity) and cognitive decline are common accompanying features, and a subset of patients has hypogonadotropic hypogonadism, in which case the presentation corresponds to the historical Gordon Holmes syndrome. Dystonia, chorea and myoclonus broaden the movement-disorder phenotype in some patients; epilepsy can occur in infancy or accompany later multisystem disease. Age at onset is highly variable, spanning infancy to adulthood
  in the series that report it, and ataxia severity does not track age at onset. Heterozygous STUB1 variants cause the allelic autosomal dominant disorder SCA48 (MONDO:0032526), curated separately; recessive and dominant variants produce similar in vitro biochemical defects and the two entities form a clinical continuum rather than sharply separated diseases.
disease_term:
  preferred_term: Autosomal recessive spinocerebellar ataxia 16
  term:
    id: MONDO:0014339
    label: autosomal recessive spinocerebellar ataxia 16
synonyms:
- SCAR16
- spinocerebellar ataxia, autosomal recessive 16
- autosomal recessive cerebellar ataxia due to STUB1 deficiency
- STUB1 autosomal recessive cerebellar ataxia
- ATX/HSP-STUB1
- CHIP-related autosomal recessive ataxia
parents:
- autosomal recessive cerebellar ataxia
- spinocerebellar ataxia
notes: 'Scope and relationship to neighbouring entries. SCAR16 (MONDO:0014339) is curated here as the STUB1 biallelic recessive ataxia. Two adjacent entries already exist and are deliberately not merged with it: Spinocerebellar Ataxia 48 (MONDO:0032526) is the allelic autosomal dominant disorder caused by heterozygous STUB1 variants, and Cerebellar Ataxia-Hypogonadism Syndrome (MONDO:0008935, Gordon Holmes syndrome) is the clinical syndrome of ataxia with hypogonadism, whose causes include RNF216, OTUD4, PNPLA6 and STUB1. Much of the SCAR16 literature is published under the Gordon Holmes name because the index STUB1 family was ascertained through hypogonadism, so papers cited here span both labels; hypogonadism is a feature of a subset of SCAR16, not a defining criterion, and Synofzik''s Caucasian cohort found neither hypogonadism nor cognitive impairment obligatory.'
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:29317501
      reference_title: Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: mutations in CHIP cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16), a fatal neurodegenerative disease characterized by truncal and limb ataxia that results in gait instability
      explanation: SCAR16 is characterised as a neurodegenerative disease whose defining manifestations are ataxia and gait instability, placing it in Harrison's neurologic Part.
pathophysiology:
- name: Biallelic STUB1 Loss-of-Function Variants
  description: Homozygous or compound heterozygous pathogenic variants in STUB1 are the initiating lesion. Variants are distributed across all three CHIP domains (tetratricopeptide-repeat, coiled-coil and U-box) and include missense, nonsense and frameshift alleles; a nonsense allele truncates the protein before the U-box and abolishes ligase activity outright.
  biological_scale: MOLECULAR
  downstream:
  - target: CHIP Structural Destabilization
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29317501
      reference_title: Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: we systematically analyzed CHIP mutations that cause SCAR16 and found that most SCAR16 mutations destabilize CHIP.
      explanation: Systematic biophysical analysis of the SCAR16 allele set establishes that the variants act on CHIP by destabilizing the protein, which is the step this edge asserts.
  - target: Loss of CHIP E3 Ubiquitin Ligase Activity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24113144
      reference_title: Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Introduction of the Thr246Met mutation into CHIP results in a loss of ubiquitin ligase activity measured directly using recombinant proteins as well as in cell culture models.
      explanation: Introducing the index SCAR16 variant into CHIP abolishes ligase activity in recombinant protein and in cells, which is a direct variant-to-enzyme-defect causal claim.
    - reference: PMID:41851873
      reference_title: A novel STUB1 p.(Gln118*) nonsense variant in compound heterozygosity causes autosomal recessive spinocerebellar ataxia type 16 in a Chinese patient.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We found that STUB1 p.(Gln118*) variant generated truncated proteins of the C-terminus of Hsc70-interacting protein and caused the loss function of ubiquitin ligase activity.
      explanation: A nonsense allele reaches the same endpoint by truncation, showing the edge holds across variant classes and not only for the index missense allele.
  - target: Impaired CHIP-HSC70 Chaperone Coupling
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25258038
      reference_title: STUB1 mutations in autosomal recessive ataxias - evidence for mutation-specific clinical heterogeneity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We show that the p.Asn65Ser substitution impairs CHIP's ability to ubiquitinate HSC70 in vitro, despite being able to self-ubiquitinate.
      explanation: A tetratricopeptide-repeat-domain variant selectively impairs handling of the chaperone substrate while leaving self-ubiquitination intact, which is the chaperone-coupling arm of the mechanism rather than a blanket loss of catalysis.
  - target: CARP-Dependent CHIP Aggregate Formation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - CARP-dependent CHIP ubiquitination
    evidence:
    - reference: PMID:36853170
      reference_title: CARPs regulate STUB1 and its pathogenic mutants aggregation kinetics by mono-ubiquitination.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: pathogenic mutants of STUB1 are more prone than the wild-type to CARP2-mediated aggregate assembly.
      explanation: CARP2 modifies mutant CHIP and promotes aggregate assembly in experimental systems; human neuronal causation is untested.
  genes:
  - preferred_term: STUB1
    term:
      id: hgnc:11427
      label: STUB1
  evidence:
  - reference: PMID:24312598
    reference_title: Identification of CHIP as a novel causative gene for autosomal recessive cerebellar ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: using a combination of whole-exome sequencing and linkage analysis, we identified CHIP, encoding a U-box containing ubiquitin E3 ligase, as a novel causative gene for autosomal recessive cerebellar ataxia.
    explanation: The gene-discovery study establishing STUB1/CHIP as the cause of this autosomal recessive cerebellar ataxia.
  - reference: PMID:28396517
    reference_title: In vitro characterization of six STUB1 variants in spinocerebellar ataxia 16 reveals altered structural properties for the encoded CHIP proteins.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Spinocerebellar ataxia, autosomal recessive 16 (SCAR16) is caused by biallelic mutations in the STIP1 homology and U-box containing protein 1 (STUB1) gene encoding the ubiquitin E3 ligase and dimeric co-chaperone C-terminus of Hsc70-interacting protein (CHIP).
    explanation: States the biallelic requirement and identifies the gene product as a dual-function E3 ligase and co-chaperone.
- name: CHIP Structural Destabilization
  description: Many tested SCAR16 variants reduce CHIP thermal stability. The p.Thr246Met U-box is structurally disorganized, whereas p.Asn65Ser has increased alpha-helical content and resistance to limited proteolysis in the 2017 study. Effects vary with allele, assay and construct; several 2017 structural experiments used an MBP fusion. Reduced steady-state abundance in cells is a distinct accompanying observation, not proof that every allele is equally unstable.
  biological_scale: MOLECULAR
  downstream:
  - target: Loss of CHIP E3 Ubiquitin Ligase Activity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30222779
      reference_title: Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: we demonstrated that T246M mutation results in structural disorganization and misfolding of the CHIP U-box domain, promoting oligomerization, and increased proteasome-dependent turnover. CHIP-T246M has no ligase activity, but maintains interactions with chaperones and chaperone-related functions.
      explanation: Ties the structural destabilization of the U-box directly to abolished ligase activity, and shows the two arms of the mechanism can dissociate because chaperone interactions are preserved in this variant.
  - target: CHIP Oligomerization
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29317501
      reference_title: Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: This destabilization caused mutation-specific defects in CHIP activity, including increased formation of soluble oligomers
      explanation: Destabilization favors oligomer formation in the biochemical experiments.
  - target: Reduced CHIP Protein Abundance
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Increased turnover of unstable CHIP
    evidence:
    - reference: PMID:30222779
      reference_title: Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: we demonstrated that T246M mutation results in structural disorganization and misfolding of the CHIP U-box domain, promoting oligomerization, and increased proteasome-dependent turnover. CHIP-T246M has no ligase activity, but maintains interactions with chaperones and chaperone-related functions.
      explanation: Ties the structural destabilization of the U-box directly to abolished ligase activity, and shows the two arms of the mechanism can dissociate because chaperone interactions are preserved in this variant.
  evidence:
  - reference: PMID:29317501
    reference_title: Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: This destabilization caused mutation-specific defects in CHIP activity, including increased formation of soluble oligomers, decreased interactions with chaperones, diminished substrate ubiquitination, and reduced steady-state levels in cells.
    explanation: 'Enumerates the consequences of destabilization that this node describes: oligomer formation, weakened chaperone interaction, less substrate ubiquitination, and lower protein abundance.'
  - reference: PMID:28396517
    reference_title: In vitro characterization of six STUB1 variants in spinocerebellar ataxia 16 reveals altered structural properties for the encoded CHIP proteins.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: our results illustrate that some STUB1 mutations known to cause recessive SCAR16 have a profound impact on the protein structure, stability, and ability of CHIP to dimerize in vitro.
    explanation: Independent biophysical characterization of six SCAR16 variants confirming effects on structure, stability and dimerization.
  - reference: PMID:28396517
    reference_title: In vitro characterization of six STUB1 variants in spinocerebellar ataxia 16 reveals altered structural properties for the encoded CHIP proteins.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: N65S shows increased CHIP dimerization, higher levels of α-helical content, and decreased degradation rate compared with wild-type (WT) CHIP.
    explanation: This allele was more resistant to limited proteolysis, contrasting with the aggregation-prone T246M protein.
- name: Reduced CHIP Protein Abundance
  description: CHIP steady-state protein levels are reduced in several patient fibroblast and mutant-expression systems, and in T246M rodent tissues. The effect varies across alleles and constructs; measured abundance does not itself identify the degradation pathway.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:25258038
    reference_title: STUB1 mutations in autosomal recessive ataxias - evidence for mutation-specific clinical heterogeneity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Furthermore, we show that the levels of CHIP are strongly reduced in vivo in patients' fibroblasts compared to controls.
    explanation: Confirms in patient-derived cells that CHIP protein abundance is reduced, not only that the enzyme is catalytically impaired.
  downstream:
  - target: Failure of Chaperone-Assisted Protein Quality Control
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced protein availability can contribute to the patient-fibroblast proteostasis defect; mutant abundance and mutant activity were not independently varied.
    evidence:
    - reference: PMID:33097556
      reference_title: CHIP mutations affect the heat shock response differently in human fibroblasts and iPSC-derived neurons.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: CHIP protein levels were confirmed to be reduced in all three patient-derived fibroblasts compared to the three healthy controls
      explanation: Reduced abundance and impaired heat-shock responses coexist in the same fibroblast panel. This does not isolate protein dosage from allele-specific functional defects.
      directness: INDIRECT
    - reference: PMID:33097556
      reference_title: CHIP mutations affect the heat shock response differently in human fibroblasts and iPSC-derived neurons.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We found impaired HSR induction and recovery compared to healthy controls.
      explanation: The fibroblast functional readout supports this indirect link; the immature cortical-neuron response differed.
      directness: INDIRECT
  - target: Excess PINK1/Parkin-Mediated Mitophagy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: CHIP knockdown produces the mitophagy phenotype in stressed U2OS/Parkin cells. Transfer to biallelic SCAR16 neurons remains hypothetical.
    evidence:
    - reference: url:https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf
      reference_title: https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: CHIP knockdown significantly increased the percentage of cells undergoing mitophagy
      explanation: 'Earnshaw et al. 2024 (PMID:39117117), recovered full text: The U2OS result required CCCP-induced mitochondrial stress and ectopic Parkin; extrapolation to SCAR16 is indirect.'
- name: CHIP Oligomerization
  description: 'Many recombinant SCAR16 proteins form higher-order soluble assemblies. This is allele-dependent: p.Asn65Ser remained predominantly dimeric in the 2018 study. Soluble oligomers and detergent-insoluble aggregates are separate experimental readouts. The experiments do not isolate oligomerization as the cause of a particular downstream patient phenotype.'
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:29317501
    reference_title: Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: increased formation of soluble oligomers
    explanation: The biochemical study measured increased soluble oligomers; this is distinct from insoluble cellular inclusions.
- name: CARP-Dependent CHIP Aggregate Formation
  description: CARP-mediated CHIP ubiquitination favors detergent-insoluble sequestration. The T246M protein shows greater insoluble accumulation than wild type during CARP2 coexpression. This cellular mechanism has not been established in patient neurons. Whether this sequestration causes neuronal injury or is protective is unresolved.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:36853170
    reference_title: CARPs regulate STUB1 and its pathogenic mutants aggregation kinetics by mono-ubiquitination.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: pathogenic mutants of STUB1 are more prone than the wild-type to CARP2-mediated aggregate assembly.
    explanation: CARP2 modifies mutant CHIP and promotes aggregate assembly in experimental systems; human neuronal causation is untested.
  mechanism_confidence: PROVISIONAL
- name: Loss of CHIP E3 Ubiquitin Ligase Activity
  description: Loss or reduction of ubiquitin ligase activity is allele- and assay-dependent. p.Thr246Met abolishes Hsc70- and self-ubiquitination while retaining chaperone interactions, but also destabilizes and oligomerizes CHIP. In the 2017 recombinant assays, p.Asn65Ser retained self-ubiquitination with impaired Hsc70 ubiquitination, whereas p.Glu28Lys, p.Lys145Gln, p.Met211Ile and p.Ser236Thr had activity similar to wild type. Preserved activity in one assay does not exclude defective cellular abundance, structure or handling of other substrates.
  biological_scale: MOLECULAR
  downstream:
  - target: Failure of Chaperone-Assisted Protein Quality Control
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24312598
      reference_title: Identification of CHIP as a novel causative gene for autosomal recessive cerebellar ataxia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Wild-type, but not disease-associated mutant CHIPs promoted the degradation of NR2A, which may underlie the pathogenesis of ataxia.
      explanation: Shows a named CHIP client escaping degradation specifically when the ligase carries a disease variant, which is the substrate-handling failure this edge asserts.
  - target: Impaired PKAc Ubiquitination and Turnover
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31189917
      reference_title: Feedback inhibition of cAMP effector signaling by a chaperone-assisted ubiquitin system.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: CHIP knockdown prevented PKAc decline following holoenzyme dissociation.
      explanation: HEK293 perturbation experiments establish CHIP-dependent PKAc turnover; patient fibroblasts establish the downstream signaling phenotype rather than directly measuring this degradation step.
  - target: Impaired NEK10 Proteolysis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29581457
      reference_title: Counterregulation of cAMP-directed kinase activities controls ciliogenesis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: wild-type CHIP, but not its catalytically inactive mutant (K30A), reduced NEK10 levels
      explanation: HEK293 biochemical experiments place CHIP downstream of PKA phosphorylation of NEK10 at T812. K30A is an experimental chaperone-binding mutant, not a patient allele.
  - target: PDE9A Accumulation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Impaired CHIP-dependent substrate ubiquitination diminishes PDE9A clearance.
    evidence:
    - reference: PMID:39806097
      reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: the T246M mutation corroborated the role of CHIP in PDE9A polyubiquitination
      explanation: Expression and domain-mutant experiments support impaired CHIP-dependent ubiquitination of PDE9A; the disease allele is p.Thr246Met, whereas K30A is an engineered control.
    intermediate_mechanisms:
    - Reduced autophagic degradation of ubiquitinated PDE9A
  molecular_functions:
  - preferred_term: ubiquitin-protein transferase activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0004842
      label: ubiquitin-protein transferase activity
  biological_processes:
  - preferred_term: protein ubiquitination
    modifier: DECREASED
    term:
      id: GO:0016567
      label: protein ubiquitination
  evidence:
  - reference: PMID:30222779
    reference_title: Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We discovered a genetic disease, now known as spinocerebellar autosomal recessive 16 (SCAR16), resulting from a coding mutation that caused a loss of CHIP ubiquitin ligase function.
    explanation: The discovery work concerns the p.Thr246Met allele; it does not establish complete catalytic loss for every SCAR16 allele.
  - reference: PMID:28396517
    reference_title: In vitro characterization of six STUB1 variants in spinocerebellar ataxia 16 reveals altered structural properties for the encoded CHIP proteins.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: The ubiquitination activities of the other mutants (E28K, K145Q, M211I, and S236T) were not overtly different from WT CHIP.
    explanation: Recombinant Hsc70- and self-ubiquitination assays retain activity for these alleles, refuting a universal catalytic-null model.
- name: Impaired CHIP-HSC70 Chaperone Coupling
  description: 'Some variants impair CHIP interactions with HSP70/HSC70 or handling of the chaperone substrate. Effects differ among TPR variants: p.Asn65Ser retains self-ubiquitination but has impaired Hsc70 ubiquitination, whereas p.Glu28Lys retains both activities in the 2017 assays. The U-box p.Thr246Met protein retains chaperone binding despite loss of ligase activity. These observations separate chaperone coupling from catalytic activity without making all variants in one domain functionally equivalent.'
  biological_scale: MOLECULAR
  downstream:
  - target: Failure of Chaperone-Assisted Protein Quality Control
    causal_link_type: DIRECT
  molecular_functions:
  - preferred_term: Hsp70 protein binding
    modifier: DECREASED
    term:
      id: GO:0030544
      label: Hsp70 protein binding
  - preferred_term: protein-folding chaperone binding
    modifier: DECREASED
    term:
      id: GO:0051087
      label: protein-folding chaperone binding
  evidence:
  - reference: PMID:25258038
    reference_title: STUB1 mutations in autosomal recessive ataxias - evidence for mutation-specific clinical heterogeneity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We show that the p.Asn65Ser substitution impairs CHIP's ability to ubiquitinate HSC70 in vitro, despite being able to self-ubiquitinate.
    explanation: A tetratricopeptide-repeat variant that specifically fails to handle the chaperone substrate while retaining self-ubiquitination is the direct demonstration that this arm of the mechanism is separable from the catalytic arm.
  - reference: PMID:29317501
    reference_title: Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: This destabilization caused mutation-specific defects in CHIP activity, including increased formation of soluble oligomers, decreased interactions with chaperones, diminished substrate ubiquitination, and reduced steady-state levels in cells.
    explanation: The decreased-chaperone-interaction clause is what supports the reduced binding recorded in this node's molecular_functions; the neighbouring clauses about oligomers and abundance belong to the destabilization node and are curated there.
  - reference: PMID:24742043
    reference_title: 'Phenotype and frequency of STUB1 mutations: next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our results expand the genotypic spectrum of STUB1-disease, showing that pathogenic mutations affect also the tetratricopeptide-repeat domain, thus providing clinical evidence for the functional importance of this domain.
    explanation: Establishes that the chaperone-binding TPR domain carries pathogenic variants in patients, so this arm of the mechanism is clinically instantiated and not only a biochemical possibility.
- name: Failure of Chaperone-Assisted Protein Quality Control
  description: Defective CHIP-dependent client handling and ubiquitination can disrupt protein turnover. Patient fibroblasts show altered heat-shock responses; patient-derived immature cortical neurons instead show proteomic pathway differences without reproducing the fibroblast response defect. These assays do not establish uniform impairment across alleles, cell types or developmental stages. A separate proposed mitophagy mechanism rests on gene perturbation and SCA48-variant models rather than direct SCAR16 evidence.
  biological_scale: CELLULAR
  downstream:
  - target: Corticospinal Tract Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24742043
      reference_title: 'Phenotype and frequency of STUB1 mutations: next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts.'
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: Pyramidal tract damage is a common accompanying feature and can include lower limb spasticity
      explanation: 'Pyramidal tract damage accompanies the cerebellar disease consistently enough to be a core feature, which places it downstream of the same CHIP proteostasis defect. Indirect and with unknown intermediates: no study shows the corticospinal degeneration is caused by the quality-control failure specifically, and the neuron-population selectivity is unexplained.'
  - target: Hypothalamic-Pituitary Gonadotropin Deficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24113144
      reference_title: Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: Loss of CHIP function in mice resulted in behavioral and reproductive impairments that mimic human ataxia and hypogonadism.
      explanation: 'Loss of CHIP function is sufficient to produce the reproductive deficit in mice, placing the endocrine branch downstream of the same molecular lesion. The intermediates are unknown: nothing localizes the defect within the hypothalamic-pituitary-gonadal axis or names the CHIP client involved, which is the open question recorded in the knowledge-gap discussion attached to that node.'
  - target: Purkinje Cell Degeneration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34630034
      reference_title: Chip Protein U-Box Domain Truncation Affects Purkinje Neuron Morphology and Leads to Behavioral Changes in Zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Mutant fish also had decreased total 26S proteasome activity in the brain and showed behavioral changes.
      explanation: In an animal carrying a U-box truncation, the proteasome-handling defect and the Purkinje phenotype reported in the same animals link the proteostasis failure to cerebellar cell pathology. Indirect because the study establishes co-occurrence in one model rather than isolating proteostasis failure as the sufficient cause of the cell loss.
    description: ' In the zebrafish truncation model, Purkinje-cell counts were already reduced at 6 months, while the measured whole-brain proteasome decline appeared only at 24 months; this experiment does not resolve the initiating causal step.'
  biological_processes:
  - preferred_term: protein quality control for misfolded or incompletely synthesized proteins
    modifier: DECREASED
    term:
      id: GO:0006515
      label: protein quality control for misfolded or incompletely synthesized proteins
  - preferred_term: ubiquitin-dependent protein catabolic process
    modifier: DECREASED
    term:
      id: GO:0006511
      label: ubiquitin-dependent protein catabolic process
  evidence:
  - reference: PMID:33097556
    reference_title: CHIP mutations affect the heat shock response differently in human fibroblasts and iPSC-derived neurons.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We found impaired HSR induction and recovery compared to healthy controls.
    explanation: Primary fibroblasts from three SCAR16 patients show a defective heat shock response, a direct patient-cell readout of disturbed proteostasis.
  - reference: PMID:33097556
    reference_title: CHIP mutations affect the heat shock response differently in human fibroblasts and iPSC-derived neurons.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Proteomic analysis of CNs showed dysfunctional protein (re)folding and higher basal oxidative stress levels in patients.
    explanation: Protein-abundance and pathway-enrichment differences in patient-derived cortical neurons support altered proteostasis responses. The full text reports proteomic inference rather than direct measurement of refolding capacity or reactive oxygen species.
- name: Purkinje Cell Degeneration
  description: Cerebellar Purkinje neurons are a major cellular target. Autopsy of a man with compound heterozygous p.Met211Ile/p.Glu238Ter STUB1 variants showed severe Purkinje and granule-cell loss with Bergmann gliosis. Experimental U-box truncation also affects Purkinje-cell number, size and dendritic organization.
  biological_scale: CELLULAR
  downstream:
  - target: Cerebellar Atrophy
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
      reference_title: https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: severe loss of Purkinje cells and neurons of the granular layer, accompanied by reactive Bergmann gliosis
      explanation: 'Bettencourt 2015 (PMID:25592071), recovered full text: Cerebellar cortical cell loss provides a pathological substrate for the progressive cerebellar atrophy documented in this family.'
    - reference: url:https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
      reference_title: https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: MRI brain scans revealed progressive midline and hemispheric cerebellar atrophy.
      explanation: 'Bettencourt 2015 (PMID:25592071), recovered full text: The same recessive family had progressive cerebellar volume loss on imaging.'
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  evidence:
  - reference: url:https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
    reference_title: https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: severe loss of Purkinje cells and neurons of the granular layer, accompanied by reactive Bergmann gliosis
    explanation: 'Bettencourt 2015 (PMID:25592071), recovered full text: Direct autopsy evidence in biallelic recessive SCAR16; this finding does not require inference from SCA48.'
  - reference: PMID:34630034
    reference_title: Chip Protein U-Box Domain Truncation Affects Purkinje Neuron Morphology and Leads to Behavioral Changes in Zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In contrast to SCAR16/SCA48 patients, no gross cerebellar atrophy was evident in mutant fish, however, these fish displayed reduced numbers and sizes of Purkinje cell bodies and abnormal organization of Purkinje cell dendrites.
    explanation: Direct demonstration that loss of Chip U-box function damages Purkinje cells. The same sentence records that gross cerebellar atrophy was absent in this model, so the model supports the cellular node without supporting the tissue-level one.
  - reference: PMID:34630034
    reference_title: Chip Protein U-Box Domain Truncation Affects Purkinje Neuron Morphology and Leads to Behavioral Changes in Zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In the brain, stub1 mRNA was predominantly detected in the cerebellum, including the Purkinje cell layer and granular layer.
    explanation: 'The gene is expressed in the Purkinje layer that degenerates, which is consistent with a cell-autonomous lesion. Expression is not degeneration: the granular layer also expresses stub1 and no granule-cell loss is reported, which is why only the Purkinje cell is bound above.'
- name: Cerebellar Atrophy
  description: Cerebellar volume loss is a characteristic MRI finding in reported SCAR16 cohorts. Brainstem or more widespread abnormalities occur in some patients; their presence is not required for diagnosis.
  biological_scale: TISSUE
  downstream:
  - target: Progressive Cerebellar Ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/
      reference_title: Hereditary Ataxia Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: Wide-based, staggering walk with difficulty performing tandem gait;
      explanation: GeneReviews lists this among cerebellar examination findings. Localization is extrapolated to SCAR16 cerebellar degeneration; MRI volume loss alone does not establish the functional intermediate.
  - target: Dysarthria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/
      reference_title: Hereditary Ataxia Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: Dysarthria (slowed or slurred articulation, variable pitch and loudness, monotonous or "scanning" speech);
      explanation: GeneReviews lists this among cerebellar examination findings. Localization is extrapolated to SCAR16 cerebellar degeneration; MRI volume loss alone does not establish the functional intermediate.
  - target: Gait Ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/
      reference_title: Hereditary Ataxia Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: Wide-based, staggering walk with difficulty performing tandem gait;
      explanation: The general hereditary-ataxia overview identifies this as a cerebellar sign. Its attribution to SCAR16 cerebellar disease is indirect; the cited SCAR16 cases establish occurrence, not a lesion-specific intervention.
  - target: Nystagmus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/
      reference_title: Hereditary Ataxia Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: Abnormal eye movements (saccade intrusions in primary gaze, nystagmus in horizontal or vertical gaze, saccade hypermetria).
      explanation: The general hereditary-ataxia overview identifies this as a cerebellar sign. Its attribution to SCAR16 cerebellar disease is indirect; the cited SCAR16 cases establish occurrence, not a lesion-specific intervention.
  - target: Cerebellar Atrophy on MRI
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32367277
      reference_title: Clinical and Genetic Characterization of Autosomal Recessive Spinocerebellar Ataxia Type 16 (SCAR16) in Taiwan.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The brain MRIs showed a marked cerebellar atrophy of the patients.
      explanation: The MRI phenotype is the imaging readout of this same tissue-level volume loss in Taiwanese SCAR16 patients.
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  evidence:
  - reference: PMID:33417001
    reference_title: Expanding the clinical spectrum of STIP1 homology and U-box containing protein 1-associated ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain MRI showed marked cerebellar atrophy in all patients.
    explanation: Cerebellar atrophy in every patient of a French series that included four SCAR16 cases.
  - reference: PMID:32367277
    reference_title: Clinical and Genetic Characterization of Autosomal Recessive Spinocerebellar Ataxia Type 16 (SCAR16) in Taiwan.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The brain MRIs showed a marked cerebellar atrophy of the patients.
    explanation: Independent confirmation in the Taiwanese SCAR16 families.
  - reference: PMID:36569391
    reference_title: MRI Findings in a Patient with Known SCAR-16 Type STUB1 Associated Cerebellar Ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: An MRI of her brain showed moderate to severe atrophy of the cerebellum and brainstem.
    explanation: A radiologically characterized SCAR16 case showing that the atrophy can extend beyond the cerebellum to the brainstem.
- name: Corticospinal Tract Involvement
  description: Pyramidal tract damage accompanies the cerebellar degeneration in a large share of patients, producing hyperreflexia and, at the more severe end, lower-limb spasticity or spastic tetraparesis. It is frequent enough that STUB1 disease belongs in the differential diagnosis of the spastic ataxias.
  biological_scale: TISSUE
  downstream:
  - target: Hyperreflexia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24742043
      reference_title: 'Phenotype and frequency of STUB1 mutations: next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: showed clinical signs of pyramidal tract damage (increased lower limb tendon reflexes
      explanation: The clinical results identify increased reflexes as a pyramidal sign in the affected brothers.
  - target: Lower Limb Spasticity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24742043
      reference_title: 'Phenotype and frequency of STUB1 mutations: next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Pyramidal tract damage is a common accompanying feature and can include lower limb spasticity
      explanation: The SCAR16 cohort explicitly localizes leg spasticity to pyramidal tract involvement.
  - target: Spastic Tetraparesis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28193273
      reference_title: 'STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: all three subjects developed severe pyramidal tract damage to arms and legs , including incapacitating tetraspasticity.
      explanation: The full-text clinical results explicitly identify four-limb spasticity as a manifestation of pyramidal damage.
  evidence:
  - reference: PMID:24742043
    reference_title: 'Phenotype and frequency of STUB1 mutations: next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All patients showed evidence of pyramidal tract damage.
    explanation: Every STUB1 ataxia patient in this Caucasian screening cohort had pyramidal tract involvement.
  - reference: PMID:28193273
    reference_title: 'STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All three subjects presented with a severe multisystemic phenotype including severe dementia, spastic tetraparesis, epilepsy, and autonomic dysfunction in addition to cerebellar ataxia, plus hypogonadism in one index patient.
    explanation: Documents spastic tetraparesis as the severe end of the corticospinal involvement, alongside the other multisystem features.
- name: Hypothalamic-Pituitary Gonadotropin Deficiency
  description: A subset of patients has hypogonadotropic hypogonadism, the feature that made the historical Gordon Holmes syndrome. Loss of CHIP function reproduces reproductive as well as motor impairment in mice, but the cellular basis of the neuroendocrine deficit in human disease has not been established, and hypogonadism is absent from whole cohorts of STUB1 ataxia. In the original T246M sisters, preserved responses to a single GnRH challenge suggested a hypothalamic contribution, but did not exclude later pituitary dysfunction.
  biological_scale: ORGANISM
  downstream:
  - target: Hypogonadotropic Hypogonadism
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:24113144
    reference_title: Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Loss of CHIP function in mice resulted in behavioral and reproductive impairments that mimic human ataxia and hypogonadism.
    explanation: Mouse loss of CHIP function produces reproductive impairment alongside the behavioural phenotype, supporting a causal rather than coincidental link between the CHIP defect and the gonadal axis.
  - reference: PMID:28193273
    reference_title: 'STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: our data reveal the second STUB1 family with ataxia plus hypogonadism reported so far, demonstrating that Gordon Holmes syndrome is indeed a recurrent manifestation of STUB1.
    explanation: Confirms in patients that the ataxia-plus-hypogonadism combination recurs in STUB1 disease rather than being confined to the index family.
  - reference: PMID:24742043
    reference_title: 'Phenotype and frequency of STUB1 mutations: next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: In contrast to previous reports, STUB1-ataxia can start even above age 40 years, and neither hypogonadism nor prominent cognitive impairment are obligatory features.
    explanation: 'Supports this node''s framing as a subset branch rather than an obligatory part of SCAR16: a screening cohort found no hypogonadism at all. Indirect because the quote establishes the branch''s optionality by absence rather than asserting the branch itself.'
- name: Excess PINK1/Parkin-Mediated Mitophagy
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: 'CHIP knockdown increases stress-induced PINK1 abundance, Parkin recruitment and mitochondrial delivery to lysosomes in U2OS cells engineered to express Parkin. Loss of the worm orthologue chn-1 increases basal neuronal mitophagy, dependent on pink-1 and pdr-1. Whether this mechanism contributes to SCAR16 Purkinje-cell disease is unconfirmed: the two patient variants tested in the 2024 study, p.Ile53Thr and p.Leu275AspfsTer16, are dominant SCA48 alleles, not recessive SCAR16 alleles. A separate 2025 T246M rat study interprets mitochondrial morphology and static autophagy markers as impaired mitophagy; these assays and genotypes differ and do not establish a single direction of flux across models.'
  biological_processes:
  - preferred_term: mitophagy
    modifier: INCREASED
    term:
      id: GO:0000423
      label: mitophagy
  evidence:
  - reference: url:https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf
    reference_title: https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: CHIP knockdown significantly increased the percentage of cells undergoing mitophagy
    explanation: 'Earnshaw et al. 2024 (PMID:39117117), recovered full text: The U2OS result required CCCP-induced mitochondrial stress and ectopic Parkin; extrapolation to SCAR16 is indirect.'
  - reference: url:https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf
    reference_title: https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: the increase in neuronal mitophagy observed in chn-1(by155) worms is dependent on both PINK1 and Parkin.
    explanation: 'Earnshaw et al. 2024 (PMID:39117117), recovered full text: Loss-of-function and double-mutant comparisons support the pathway in worm neurons, not its causal role in human SCAR16.'
- name: Impaired PKAc Ubiquitination and Turnover
  biological_scale: MOLECULAR
  description: CHIP-dependent ubiquitination and proteasomal turnover of activated PKA catalytic subunits are impaired by CHIP loss in cell models. PKAc Lys310 is the principal ubiquitin acceptor identified in the 2019 study. This substrate-specific regulatory mechanism is distinct from clearance of misfolded proteins; its downstream signaling defect is observed in SCAR16 fibroblasts.
  biological_processes:
  - preferred_term: protein ubiquitination
    term:
      id: GO:0016567
      label: protein ubiquitination
    modifier: DECREASED
  evidence:
  - reference: PMID:31189917
    reference_title: Feedback inhibition of cAMP effector signaling by a chaperone-assisted ubiquitin system.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: CHIP knockdown prevented PKAc decline following holoenzyme dissociation.
    explanation: HEK293 perturbation experiments establish CHIP-dependent PKAc turnover; patient fibroblasts establish the downstream signaling phenotype rather than directly measuring this degradation step.
  downstream:
  - target: Elevated Basal PKA-CREB Signaling
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31189917
      reference_title: Feedback inhibition of cAMP effector signaling by a chaperone-assisted ubiquitin system.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The K310A mutation enhanced CREB phosphorylation and c-fos transcription
      explanation: Blocking the identified PKAc ubiquitination site reproduces increased downstream signaling, supporting the link from failed turnover to altered signaling.
  mechanism_confidence: PROVISIONAL
- name: Elevated Basal PKA-CREB Signaling
  biological_scale: CELLULAR
  description: SCAR16 patient fibroblasts have elevated basal CREB phosphorylation with little additional response to forskolin. PKA inhibition reduces this phosphorylation phenotype. CHIP perturbation and hippocampal slice studies support a signaling role, but these experiments do not prove that this pathway causes human Purkinje-cell loss or hypogonadism. The measured fibroblast signaling state has not been linked causally to an individual SCAR16 clinical manifestation.
  evidence:
  - reference: PMID:31189917
    reference_title: Feedback inhibition of cAMP effector signaling by a chaperone-assisted ubiquitin system.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: STUB1 mutations, like CHIP downregulation, increased basal levels of phosphoCREB-positive nuclei that could not be further induced by FSK.
    explanation: Primary fibroblasts from two SCAR16 patients, AX71 and AX29, show altered basal signaling and response to forskolin. These are cell-culture readouts, not clinical biomarkers.
  - reference: PMID:31189917
    reference_title: Feedback inhibition of cAMP effector signaling by a chaperone-assisted ubiquitin system.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In SCAR16 fibroblasts, inhibition of PKA activity reversed the effects of CHIP mutations on CREB phosphorylation
    explanation: H89 reverses a biochemical patient-cell readout; clinical efficacy was not investigated.
  mechanism_confidence: PROVISIONAL
- name: Impaired NEK10 Proteolysis
  biological_scale: MOLECULAR
  description: Cellular CHIP deficiency interferes with degradation of the pro-ciliogenic kinase NEK10. In the reconstructed pathway, PKA phosphorylation of NEK10 at T812 primes its CHIP-dependent ubiquitination and proteolysis. The pathway is supported by HEK293 perturbations and by downstream ciliary phenotypes in SCAR16 fibroblasts.
  biological_processes:
  - preferred_term: protein ubiquitination
    term:
      id: GO:0016567
      label: protein ubiquitination
    modifier: DECREASED
  evidence:
  - reference: PMID:29581457
    reference_title: Counterregulation of cAMP-directed kinase activities controls ciliogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: wild-type CHIP, but not its catalytically inactive mutant (K30A), reduced NEK10 levels
    explanation: HEK293 biochemical experiments place CHIP downstream of PKA phosphorylation of NEK10 at T812. K30A is an experimental chaperone-binding mutant, not a patient allele.
  - reference: PMID:29581457
    reference_title: Counterregulation of cAMP-directed kinase activities controls ciliogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: genetic silencing of endogenous CHIP (Fig. 6f) prevented FSK-induced NEK10 poly-ubiquitination.
    explanation: Endogenous CHIP knockdown supports the same substrate-ubiquitination dependence as the K30A construct.
  downstream:
  - target: Impaired cAMP-Induced Cilium Resorption
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29581457
      reference_title: Counterregulation of cAMP-directed kinase activities controls ciliogenesis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: genetic silencing of NEK10 in SCAR16 fibroblasts markedly reduced the number of ciliated cells, even in the absence of FSK
      explanation: Reducing NEK10 reverses ciliary persistence in the patient-cell setting, supporting the proposed substrate-to-organelle link.
  mechanism_confidence: PROVISIONAL
- name: Impaired cAMP-Induced Cilium Resorption
  biological_scale: CELLULAR
  description: Serum-starved SCAR16 AX71 fibroblasts show impaired primary-cilium resorption after forskolin stimulation. NEK10 knockdown reduces their ciliated-cell fraction. The finding depends on culture conditions; the study reports different cAMP effects in serum-supplemented confluent cells. Its contribution to human neurological or endocrine disease remains unresolved. A causal contribution of this fibroblast ciliary phenotype to cerebellar degeneration has not been demonstrated.
  biological_processes:
  - preferred_term: cilium disassembly
    term:
      id: GO:0061523
      label: cilium disassembly
    modifier: DECREASED
  evidence:
  - reference: PMID:29581457
    reference_title: Counterregulation of cAMP-directed kinase activities controls ciliogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: no major effects of FSK stimulation on cilia were evident in SCAR16 fibroblasts.
    explanation: Under serum starvation, control fibroblasts resorb cilia after forskolin, whereas the SCAR16 AX71 model does not. This does not establish a clinical ciliopathy diagnosis.
  mechanism_confidence: PROVISIONAL
- name: PDE9A Accumulation
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: PDE9A protein accumulates in the homozygous T246M rat model and CHIP-perturbed HEK293T cells. CHIP normally promotes K63- and K27-linked ubiquitination of PDE9A at Lys186 and its autophagic clearance. The 2025 study supports this substrate-specific pathway as a candidate contributor to SCAR16, without human patient confirmation.
  biological_processes:
  - preferred_term: protein ubiquitination
    modifier: DECREASED
    term:
      id: GO:0016567
      label: protein ubiquitination
  evidence:
  - reference: PMID:39806097
    reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Mutation of PDE9A at K186R disrupted CHIP-mediated ubiquitination, resulting in an increased half-life and overaccumulation of PDE9A in cells
    explanation: Substrate-site mutagenesis connects ubiquitination to PDE9A turnover. Bafilomycin and bortezomib comparisons support autophagic rather than proteasomal degradation of PDE9A in this system.
  - reference: PMID:39806097
    reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: the levels of CHIP, cGMP, PKG1 and PKG2 were diminished in the Hom group, and the PDE9A level was increased
    explanation: Rat cerebellar and hippocampal measurements include cGMP ELISA and protein assays. These establish the model state; they are not patient biomarker measurements.
  downstream:
  - target: Reduced cGMP Availability
    causal_link_type: DIRECT
    description: PDE9A-mediated cGMP hydrolysis provides the proposed biochemical link.
    evidence:
    - reference: PMID:39806097
      reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: PDE9A accumulation, increased cGMP hydrolysis
      explanation: The study proposes that excess PDE9A increases hydrolysis of its cGMP substrate; rat cGMP concentrations and response to PDE9A inhibition support this model.
  - target: Mitochondrial Structural Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: PDE9A inhibition improves mitochondrial injury in the mutant rat; the intervening causal steps are not isolated by these experiments.
    evidence:
    - reference: PMID:39806097
      reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Treatment with Bay 73-6691 or AAV-CHIP resulted in a reduction in scores, indicating mitigated mitochondrial damage and morphological improvements in the mutated rats
      explanation: Electron microscopy and Flameng scoring establish mitochondrial structural injury and its improvement in the treated rat cohorts. Static morphology and marker levels do not directly measure mitophagic flux.
- name: Reduced cGMP Availability
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: cGMP concentrations are reduced in cerebellar and hippocampal tissue of homozygous T246M rats. Reduced PKG1/PKG2 abundance and transcriptomic pathway scores accompany this state. These measurements should not be equated with direct PKG enzyme-activity assays.
  evidence:
  - reference: PMID:39806097
    reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: the levels of CHIP, cGMP, PKG1 and PKG2 were diminished in the Hom group, and the PDE9A level was increased
    explanation: Rat cerebellar and hippocampal measurements include cGMP ELISA and protein assays. These establish the model state; they are not patient biomarker measurements.
  downstream:
  - target: Reduced CHIP Serine Phosphorylation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: The proposed cGMP-PKG pathway links PDE9A inhibition to restored CHIP phosphorylation.
    evidence:
    - reference: PMID:39806097
      reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: After the inhibition of PDE9A with Bay 73-6691, a conspicuous increase in CHIP S20 phosphorylation was detected
      explanation: The phospho-specific antibody detects the rodent S20 site, corresponding to human S19. Inhibitor and AAV interventions support the feedback model.
    intermediate_mechanisms:
    - PKG-dependent phosphorylation of CHIP
- name: Reduced CHIP Serine Phosphorylation
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: CHIP phosphorylation at the rodent Ser20 site is reduced in the T246M rat model and increases after PDE9A inhibition or AAV-CHIP treatment. This corresponds to human Ser19. The study proposes reduced phosphorylation-dependent CHIP stability as a reinforcing feedback loop; relevance across the human allelic spectrum remains untested.
  evidence:
  - reference: PMID:39806097
    reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: After the inhibition of PDE9A with Bay 73-6691, a conspicuous increase in CHIP S20 phosphorylation was detected
    explanation: The phospho-specific antibody detects the rodent S20 site, corresponding to human S19. Inhibitor and AAV interventions support the feedback model.
  downstream:
  - target: Reduced CHIP Protein Abundance
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced phosphorylation-dependent CHIP stability
    description: Proposed positive feedback in the rat study; the phosphorylation and stability steps have not been isolated across SCAR16 patient alleles.
    evidence:
    - reference: PMID:39806097
      reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: This increases PDE9A levels, resulting in cGMP hydrolysis, inhibition of CHIP S19 phosphorylation and decreased CHIP stability.
      explanation: The study discussion proposes reduced CHIP stability as the consequence of diminished phosphorylation; the rat interventions support the feedback model indirectly.
      directness: INDIRECT
- name: Mitochondrial Structural Injury
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: T246M rat cerebellar tissue shows swollen mitochondria, cristae disruption and vacuolization. Increased p62 and FIS1 and reduced LC3B, OPA1 and BNIP3 accompany the ultrastructural injury. PDE9A inhibition or CHIP gene delivery improves these readouts. The authors interpret them as disturbed mitophagy, but the study does not directly quantify mitophagic flux; it therefore does not settle the direction of mitochondrial clearance in human SCAR16. The experiments do not isolate this structural injury as the cause of Purkinje-cell loss.
  evidence:
  - reference: PMID:39806097
    reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Treatment with Bay 73-6691 or AAV-CHIP resulted in a reduction in scores, indicating mitigated mitochondrial damage and morphological improvements in the mutated rats
    explanation: Electron microscopy and Flameng scoring establish mitochondrial structural injury and its improvement in the treated rat cohorts. Static morphology and marker levels do not directly measure mitophagic flux.
  - reference: PMID:39806097
    reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: increased P62 and decreased LC3B levels were detected in both the hippocampus and cerebellum
    explanation: The measured static markers support altered autophagy-associated states, not a direct rate measurement.
phenotypes:
- category: Neurologic
  name: Progressive Cerebellar Ataxia
  description: Progressive truncal, gait and limb ataxia is the defining clinical feature. The 2019 published-case analysis reported median onset at 17 years, with a range of 0.5 to 49 years; these are cohort-specific observations rather than fixed diagnostic age limits.
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
    clinical_course: PROGRESSIVE
    onset:
      onset_category: JUVENILE
      min_age_years: 0.5
      max_age_years: 49.0
      notes: Median 17 years, range 0.5–49, in the SCAR16 patient set assembled by Madrigal 2019. The median is not an arithmetic mean. The juvenile category summarizes that median; individual onset spans infancy to adulthood. The French 14–76-year range combines SCAR16 and SCA48 and is not used here.
  frequency: VERY_FREQUENT
  sequelae:
  - target: Dysarthria
  evidence:
  - reference: PMID:33417001
    reference_title: Expanding the clinical spectrum of STIP1 homology and U-box containing protein 1-associated ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we report four SCAR16 and nine SCA48 patients from two SCAR16 and five SCA48 unrelated French families. All presented with slowly progressive cerebellar ataxia.
    explanation: All thirteen patients, including the four SCAR16 cases, had slowly progressive cerebellar ataxia, supporting the VERY_FREQUENT band.
  - reference: PMID:29317501
    reference_title: Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: in humans, mutations in CHIP cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16), a fatal neurodegenerative disease characterized by truncal and limb ataxia that results in gait instability
    explanation: Characterizes the disease by truncal and limb ataxia producing gait instability, which is the phenotype described here.
  - reference: PMID:33417001
    reference_title: Expanding the clinical spectrum of STIP1 homology and U-box containing protein 1-associated ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The age at onset was highly variable, ranging from 14 to 76 years.
    explanation: Documents how wide the onset range runs across STUB1 disease. It is not used to set this entry's recorded range because the cohort combines SCAR16 and SCA48 patients.
  - reference: PMID:31619515
    reference_title: Changes in protein function underlie the disease spectrum in patients with CHIP mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We found that the severity of ataxia did not correlate with age of onset
    explanation: Supports the statement that severity does not track age at onset, which distinguishes SCAR16 from the polyglutamine ataxias.
  - reference: PMID:31619515
    reference_title: Changes in protein function underlie the disease spectrum in patients with CHIP mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The median AOO was 17 years of age (range = 0.5-49)
    explanation: Source of the recorded onset median and range. This is a SCAR16-only patient set, which is why it is preferred here over the combined SCAR16/SCA48 range reported by the French series.
- category: Neurologic
  name: Gait Ataxia
  description: Gait instability is a common presenting feature; motor delay, epilepsy or other manifestations can precede ataxia in some families.
  phenotype_term:
    preferred_term: Gait ataxia
    term:
      id: HP:0002066
      label: Gait ataxia
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:29317501
    reference_title: Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: characterized by truncal and limb ataxia that results in gait instability
    explanation: Names gait instability as the functional consequence characterizing the disease.
- category: Neurologic
  name: Dysarthria
  description: Cerebellar dysarthria accompanies ataxia in reported recessive families. The Gordon Holmes review is enriched for endocrine presentations and does not establish a frequency across all SCAR16.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:42080998
    reference_title: 'Clinical and Genetic Profile of Gordon-Holmes Syndrome: A Review of Published Cases : Original Article.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cerebellar ataxia and dysarthria were seen in all variants.
    explanation: A review of published Gordon Holmes syndrome cases, including the five with STUB1 variants, found dysarthria in every genetic subgroup.
- category: Neurologic
  name: Cerebellar Atrophy on MRI
  description: Marked cerebellar atrophy is a characteristic imaging finding in reported SCAR16 cohorts. Brainstem atrophy occurs in some cases; its presence is not required for diagnosis.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  reports_on:
  - target: Cerebellar Atrophy
    relationship: READOUT_OF
  evidence:
  - reference: PMID:33417001
    reference_title: Expanding the clinical spectrum of STIP1 homology and U-box containing protein 1-associated ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain MRI showed marked cerebellar atrophy in all patients.
    explanation: Present in all patients of the French series, supporting VERY_FREQUENT.
  - reference: PMID:32367277
    reference_title: Clinical and Genetic Characterization of Autosomal Recessive Spinocerebellar Ataxia Type 16 (SCAR16) in Taiwan.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The brain MRIs showed a marked cerebellar atrophy of the patients.
    explanation: Independent confirmation in the Taiwanese SCAR16 patients.
- category: Neurologic
  name: Cognitive Decline
  description: Cognitive impairment, ranging from a frontal-dysexecutive profile to frank dementia, is a common but not obligatory accompaniment. It is part of the recognized SCAR16 disease spectrum, and severe dementia occurs at the multisystemic end. The relative contributions of cerebral and cerebellar pathology to cognitive decline have not been isolated in these patients.
  phenotype_term:
    preferred_term: Cognitive decline
    term:
      id: HP:0001268
      label: Mental deterioration
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:31619515
    reference_title: Changes in protein function underlie the disease spectrum in patients with CHIP mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The disease spectrum of SCAR16 includes a varying age of disease onset, cognitive dysfunction, increased tendon reflex, and hypogonadism.
    explanation: Places cognitive dysfunction in the recognized SCAR16 spectrum alongside the other accompanying features curated here.
  - reference: PMID:32367277
    reference_title: Clinical and Genetic Characterization of Autosomal Recessive Spinocerebellar Ataxia Type 16 (SCAR16) in Taiwan.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinically, the three patients from the two SCAR16 families presented with cerebellar ataxia alone or in combination with cognitive impairment.
    explanation: Cognitive impairment accompanied ataxia in some Taiwanese patients, whereas others had isolated ataxia.
  - reference: PMID:24742043
    reference_title: 'Phenotype and frequency of STUB1 mutations: next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: In contrast to previous reports, STUB1-ataxia can start even above age 40 years, and neither hypogonadism nor prominent cognitive impairment are obligatory features.
    explanation: The screening cohort found cognitive impairment in one of three affected subjects, demonstrating variability rather than an obligatory feature.
  sequelae:
  - target: Mutism
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Progressive loss of language
    evidence:
    - reference: PMID:28193273
      reference_title: 'STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: loss of language in the first three decades of life, leading to mutism in 2/3 cases before the age of 40.
      explanation: The longitudinal clinical narrative links progressive language loss in severe dementia to mutism.
- category: Neurologic
  name: Hyperreflexia
  description: Increased tendon reflexes accompany pyramidal involvement. A published SCAR16 synthesis reports increased tendon reflexes and/or cognitive dysfunction in over 70% of patients; the combined statistic does not give the frequency of either finding separately. Lower-limb spasticity is described separately.
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  evidence:
  - reference: PMID:41851873
    reference_title: A novel STUB1 p.(Gln118*) nonsense variant in compound heterozygosity causes autosomal recessive spinocerebellar ataxia type 16 in a Chinese patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The age at onset was 27 years old with clinical characteristics of cerebellar ataxia and increased tendon reflex.
    explanation: A genetically confirmed SCAR16 patient with increased tendon reflex alongside the ataxia.
  - reference: PMID:31619515
    reference_title: Changes in protein function underlie the disease spectrum in patients with CHIP mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: hypogonadism was found in only four patients, whereas over 70% of the patients suffered from increased tendon reflex and/or cognitive dysfunction
    explanation: The combined increased-reflex and/or cognitive-dysfunction statistic cannot establish the marginal frequency of hyperreflexia.
  - reference: PMID:31619515
    reference_title: Changes in protein function underlie the disease spectrum in patients with CHIP mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: cognitive dysfunction, increased tendon reflex, and ancestry were able to predict 54% of the variation in ataxia severity
    explanation: A model fitted to published clinical reports explained 54% of SARA-score variation. Some SARA scores were imputed; ancestry may be confounded by care and environmental differences. This is a cohort association, not a validated individual prognostic tool.
- category: Neurologic
  name: Lower Limb Spasticity
  description: Spasticity of the legs occurs as part of the pyramidal tract involvement and places STUB1 disease in the differential diagnosis of the spastic ataxias; the most severely affected patients develop spastic tetraparesis.
  phenotype_term:
    preferred_term: Lower limb spasticity
    term:
      id: HP:0002061
      label: Lower limb spasticity
  evidence:
  - reference: PMID:24742043
    reference_title: 'Phenotype and frequency of STUB1 mutations: next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Pyramidal tract damage is a common accompanying feature and can include lower limb spasticity
    explanation: States that the pyramidal involvement can extend to lower-limb spasticity.
  - reference: PMID:28193273
    reference_title: 'STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All three subjects presented with a severe multisystemic phenotype including severe dementia, spastic tetraparesis, epilepsy, and autonomic dysfunction in addition to cerebellar ataxia, plus hypogonadism in one index patient.
    explanation: Records spastic tetraparesis, the severe end of the same spectrum, in all three subjects of the multisystemic STUB1 families.
- category: Neurologic
  name: Peripheral Neuropathy
  description: Peripheral nerve involvement is variable. Sensory axonal neuropathy was documented in a p.Met240Thr patient, while other biallelic patients had normal nerve-conduction studies. The pathway from CHIP dysfunction to peripheral sensory axon injury is unresolved.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:24742043
    reference_title: 'Phenotype and frequency of STUB1 mutations: next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: electrophysiological evidence of sensory axonal peripheral neuropathy.
    explanation: Direct peripheral-neuropathy evidence in subject 91078; no population frequency is inferred.
  - reference: PMID:32342324
    reference_title: 'Spinocerebellar ataxia type 48: last but not least.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: SCAR16 is characterized by early onset spastic ataxia and a wide disease spectrum, including cognitive dysfunction, hyperkinetic disorders, epilepsy, peripheral neuropathy, and hypogonadism.
    explanation: The review includes peripheral neuropathy in the SCAR16 spectrum without providing a frequency estimate.
- category: Neurologic
  name: Tremor
  description: Head and hand tremor are described among the accompanying features of STUB1 recessive ataxia. The published description does not localize this head and hand tremor to a specific cerebellar or extrapyramidal mechanism.
  phenotype_term:
    preferred_term: Tremor
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: PMID:34070858
    reference_title: Genetic Dominant Variants in STUB1, Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: head and hand tremor, hyperreflexia, cognitive decline, and, occasionally, hypogonadism
    explanation: This background summary describes head and hand tremor in SCAR16; it is not a measured frequency in the functional study.
- category: Endocrine
  name: Hypogonadotropic Hypogonadism
  description: Hypogonadotropic hypogonadism, with infertility, occurs in a subset and can precede the ataxia. Its presence defines the historical Gordon Holmes syndrome presentation of STUB1 disease; entire cohorts of STUB1 ataxia have been reported without it.
  phenotype_term:
    preferred_term: Hypogonadotropic hypogonadism
    term:
      id: HP:0000044
      label: Hypogonadotropic hypogonadism
  evidence:
  - reference: PMID:25258038
    reference_title: STUB1 mutations in autosomal recessive ataxias - evidence for mutation-specific clinical heterogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: secondary infertility due to hypogonadotrophic hypogonadism.
    explanation: A woman with p.Glu28Lys/p.Lys144Ter developed secondary infertility before progressive adult-onset ataxia.
  - reference: PMID:32367277
    reference_title: Clinical and Genetic Characterization of Autosomal Recessive Spinocerebellar Ataxia Type 16 (SCAR16) in Taiwan.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: Mutations in STUB1 have been identified to cause autosomal recessive spinocerebellar ataxia type 16 (SCAR16), also named as Gordon Holmes syndrome, which is characterized by cerebellar ataxia, cognitive decline, and hypogonadism.
    explanation: 'A nosological definition of the entity, not an observation: this is the paper''s background sentence, and its own three patients had no hypogonadism. Graded OTHER and INDIRECT because it establishes that hypogonadism belongs to the recognized SCAR16 description, not that any patient in this study had it.'
  - reference: PMID:42080998
    reference_title: 'Clinical and Genetic Profile of Gordon-Holmes Syndrome: A Review of Published Cases : Original Article.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hypogonadotrophic hypogonadism were seen in all variants.
    explanation: In the published Gordon Holmes syndrome case series, hypogonadotropic hypogonadism occurred across every causal gene including STUB1. Note that this review is ascertained on the Gordon Holmes phenotype, so it speaks to the hypogonadism-defined subset, not to unselected SCAR16.
  - reference: PMID:24742043
    reference_title: 'Phenotype and frequency of STUB1 mutations: next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: Cognitive impairment was present only in one and hypogonadism in none of them.
    explanation: None of three screened index cases had hypogonadism. This establishes non-obligatory expression, but does not estimate its frequency in the whole disorder.
- category: Neurologic
  name: Seizures
  description: Epilepsy has been reported in SCAR16, including infancy in a p.Asn65Ser patient whose seizures ceased after early childhood. It also accompanies severe multisystem disease. A Gordon Holmes case review found seizures only in its STUB1 subgroup; that ascertained sample does not establish biological exclusivity across all causes. In the 2017 three-patient series, two seizure histories were confirmed and one was uncertain. The epileptogenic circuit and its connection to the measured CHIP-dependent cellular defects remain undetermined.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:25258038
    reference_title: STUB1 mutations in autosomal recessive ataxias - evidence for mutation-specific clinical heterogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She was born prematurely and had epilepsy (generalized)
    explanation: The p.Asn65Ser sister had generalized epilepsy from infancy; the subsequent narrative reports no further seizures after early childhood.
  - reference: PMID:42080998
    reference_title: 'Clinical and Genetic Profile of Gordon-Holmes Syndrome: A Review of Published Cases : Original Article.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Seizures were seen only in STUB1 variants.
    explanation: Seizures occurred only in STUB1 cases within this reviewed Gordon Holmes sample; this does not prove exclusivity or estimate frequency in unselected SCAR16.
  - reference: PMID:28193273
    reference_title: 'STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Epilepsy GTCS in early childhood GTCS (onset 35y) GTCS? (onset 42y)
    explanation: Table 2 documents generalized tonic-clonic seizures in two patients and marks the third history as GTCS?, indicating uncertainty. The abstract bundles epilepsy with the three-patient phenotype and should not be read as three confirmed cases.
- category: Neurologic
  name: Dysphagia
  description: Swallowing difficulty develops as the disease advances and is a source of aspiration risk. These multisystem cases do not establish whether cerebellar, brainstem or other motor-pathway injury is the principal cause of swallowing dysfunction.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:28193273
    reference_title: 'STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: necessitating gastric tube feeding in both subjects from family 2 at the age of 36 and 43, respectively.
    explanation: All three recessive cases developed severe dysphagia; two required enteral feeding.
  - reference: url:https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
    reference_title: https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: severe neurogenic dysphagia, which led to aspiration pneumonia and death.
    explanation: 'Bettencourt 2015 (PMID:25592071), recovered full text: The proband developed severe dysphagia late in the course; this supplies direct recessive-case evidence.'
- name: Myoclonus
  category: Neurologic
  description: Myoclonus accompanied progressive ataxia in both affected siblings of the p.Met211Ile/p.Glu238Ter family. It was also described in a separate p.Met240Thr patient; a cortical origin was suspected but not electrophysiologically confirmed. The proposed cortical generator has not been confirmed or linked to a particular CHIP-dependent cellular defect.
  phenotype_term:
    preferred_term: Myoclonus
    term:
      id: HP:0001336
      label: Myoclonus
  evidence:
  - reference: url:https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
    reference_title: https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ataxia, spasticity, myoclonus, and cognitive deterioration
    explanation: 'Bettencourt 2015 (PMID:25592071), recovered full text: Direct observation in the recessive Spanish family.'
  - reference: PMID:24742043
    reference_title: 'Phenotype and frequency of STUB1 mutations: next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Subject 91078 showed myoclonic jerks in the face and the left arm.
    explanation: A separate p.Met240Thr patient had myoclonus; cortical localization remained a hypothesis.
- name: Chorea
  category: Neurologic
  description: Choreatic or choreoathetotic movements occur in some recessive cases. Mild generalized chorea was described in the p.Met211Ile/p.Glu238Ter family, and choreoathetosis in two p.Lys145Gln/p.Pro243Leu siblings. These small series do not establish a population frequency. The clinical reports do not establish the responsible basal-ganglia lesion or molecular intermediate.
  phenotype_term:
    preferred_term: Chorea
    term:
      id: HP:0002072
      label: Chorea
  evidence:
  - reference: url:https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
    reference_title: https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She later presented with cognitive impairment that progressed to dementia, mild generalized choreatric movements
    explanation: 'Bettencourt 2015 (PMID:25592071), recovered full text: Direct observation in the recessive Spanish family.'
  - reference: PMID:28193273
    reference_title: 'STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Extrapyramidal hyperkinetic movement disorders included choreo-athetotic movements in 2/3 subjects and dystonia in 1/3 subjects.
    explanation: The full clinical results assign the choreoathetotic movements to the two affected siblings in family 2.
- name: Delayed Gross Motor Development
  category: Neurologic
  description: Early motor delay preceded the later progressive ataxia in the homozygous p.Asn65Ser family. Both the index brother and younger sister walked independently at about two and a half years. The early developmental impairment has not been mechanistically separated from later neurodegeneration.
  phenotype_term:
    preferred_term: Delayed gross motor development
    term:
      id: HP:0002194
      label: Delayed gross motor development
  evidence:
  - reference: PMID:25258038
    reference_title: STUB1 mutations in autosomal recessive ataxias - evidence for mutation-specific clinical heterogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Motor development has been slow.
    explanation: The younger sister had delayed walking and slow acquisition of motor abilities; the full clinical narrative also documents delayed walking in the index brother.
- name: High-Frequency Sensorineural Hearing Impairment
  category: Neurologic
  description: Very mild high-frequency sensorineural hearing loss was measured in two p.Asn65Ser siblings. The authors compared it with presbyacusis; this family observation does not establish a universal aging mechanism. The auditory site of injury and its molecular connection to CHIP dysfunction are unresolved.
  phenotype_term:
    preferred_term: High-frequency sensorineural hearing impairment
    term:
      id: HP:0001757
      label: High-frequency sensorineural hearing impairment
  evidence:
  - reference: PMID:25258038
    reference_title: STUB1 mutations in autosomal recessive ataxias - evidence for mutation-specific clinical heterogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Pure tone audiometry indicated very mild sensorineural hearing loss in the high frequencies
    explanation: Audiometry in the younger sister documented this finding, comparable to the result in her brother.
- name: Thin Corpus Callosum
  category: Neurologic
  description: Corpus-callosum thinning or atrophy accompanies cerebellar involvement in some patients. The p.Asn65Ser family report describes anterior-predominant thinning in the narrative, while its table describes posterior thinning for the index case; regional specificity is therefore not generalized. The imaging observation does not distinguish a developmental axonal defect from later degeneration or identify the intervening cellular mechanism.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:25258038
    reference_title: STUB1 mutations in autosomal recessive ataxias - evidence for mutation-specific clinical heterogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a distinct thinning of the anterior part of the corpus callosum
    explanation: The discussion documents thinning but explicitly leaves progression and mutation specificity unresolved.
- name: Nystagmus
  category: Neurologic
  description: Horizontal nystagmus was reported in two p.Asn65Ser siblings. Other recessive families also show nystagmus, although it is absent in some affected relatives.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:25258038
    reference_title: STUB1 mutations in autosomal recessive ataxias - evidence for mutation-specific clinical heterogeneity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Horizontal nystagmus; mild retinal atrophy
    explanation: Table 1 records horizontal nystagmus in the index brother and younger sister; no population frequency is inferred.
- name: Arm Dystonia
  category: Neurologic
  description: Focal upper-limb dystonia was documented in the p.Arg119Ter/p.Ile294Phe patient with severe multisystem SCAR16. The responsible circuit lesion has not been localized in this patient.
  phenotype_term:
    preferred_term: Arm dystonia
    term:
      id: HP:0031960
      label: Arm dystonia
  evidence:
  - reference: PMID:28193273
    reference_title: 'STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hyperkinetic movements (dystonia/athetosis) focal dystonia upper limb
    explanation: Table 2 identifies focal arm dystonia in family 1, establishing a direct recessive-case observation.
- name: Spastic Tetraparesis
  category: Neurologic
  description: Severe pyramidal involvement can affect all four limbs. All three patients in the 2017 severe multisystem series developed incapacitating tetraspasticity.
  phenotype_term:
    preferred_term: Spastic tetraparesis
    term:
      id: HP:0001285
      label: Spastic tetraparesis
  evidence:
  - reference: PMID:28193273
    reference_title: 'STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All three subjects presented with a severe multisystemic phenotype including severe dementia, spastic tetraparesis
    explanation: The abstract and full clinical results document four-limb spastic impairment in the three recessive patients.
- name: Mutism
  category: Neurologic
  description: Progressive language loss led to mutism before age 40 in two siblings with p.Lys145Gln/p.Pro243Leu and severe dementia.
  phenotype_term:
    preferred_term: Mutism
    term:
      id: HP:0002300
      label: Mutism
  evidence:
  - reference: PMID:28193273
    reference_title: 'STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: leading to mutism in 2/3 cases before the age of 40.
    explanation: The clinical narrative describes acquired loss of speech in two previously verbal patients.
- name: Urge Incontinence
  category: Genitourinary
  description: Urge incontinence was recorded in all three patients of the 2017 severe multisystem series and in other recessive families. The reports do not localize the bladder-control pathway responsible for this autonomic manifestation.
  phenotype_term:
    preferred_term: Urinary incontinence
    term:
      id: HP:0000020
      label: Urinary incontinence
  evidence:
  - reference: PMID:28193273
    reference_title: 'STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Urge incontinence + + + (40y) Parkinsonism hypomimia - -
    explanation: The urge-incontinence row contains positive entries for all three patients. The following parkinsonism row is retained only for quote context and is not generalized across the cases.
- name: Juvenile Cataract
  category: Ophthalmologic
  description: One p.Lys145Gln/p.Pro243Leu patient underwent cataract surgery at age 11, preceding ataxia at age 20. This single observation does not establish a common feature. A causal relationship between this early lens opacity and STUB1 dysfunction has not been established.
  phenotype_term:
    preferred_term: Juvenile cataract
    term:
      id: HP:0001118
      label: Juvenile cataract
  evidence:
  - reference: PMID:28193273
    reference_title: 'STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: cataracts requiring surgery at the age of 11.
    explanation: The clinical narrative documents childhood cataract in one recessive case.
genetic:
- name: STUB1 variants associated with recessive ataxia
  notes: SCAR16 requires two pathogenic STUB1 alleles, homozygous or compound heterozygous. Reported alleles span the tetratricopeptide-repeat, coiled-coil and U-box domains and include missense, nonsense and frameshift changes; the index allele is the U-box missense p.Thr246Met. Heterozygous STUB1 variants cause the allelic dominant disorder SCA48, and some alleles have been reported in both inheritance contexts. Similar biochemical defects alone cannot establish inheritance or predict clinical disease in a heterozygous relative; segregation, age and the specific allele require assessment. A 2019 analysis associated U-box disease alleles with cognitive dysfunction, but it analyzed alleles rather than independent patients and used published cases with some imputed SARA scores. Its ancestry association does not identify a genetic modifier and may be confounded by care or environmental differences. The c.612+11C>G allele below remains a source-classified VUS; its inclusion records the reported uniparental-isodisomy case and does not upgrade it to a proven disease allele.
  gene_term:
    preferred_term: STUB1
    term:
      id: hgnc:11427
      label: STUB1
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:24312598
    reference_title: Identification of CHIP as a novel causative gene for autosomal recessive cerebellar ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Using Sanger sequencing, we also identified two compound heterozygous mutations
    explanation: Compound heterozygous STUB1 alleles in additional kindreds establish the biallelic requirement beyond the homozygous index family.
  - reference: PMID:28396517
    reference_title: In vitro characterization of six STUB1 variants in spinocerebellar ataxia 16 reveals altered structural properties for the encoded CHIP proteins.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: six previously reported pathogenic STUB1 variants (E28K, N65S, K145Q, M211I, S236T, and T246M) were expressed as recombinant proteins
    explanation: Names the recurrent SCAR16 allele set that spans the three CHIP domains.
  - reference: PMID:34070858
    reference_title: Genetic Dominant Variants in STUB1, Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: These studies revealed that dominantly and recessively inherited STUB1 variants showed similar biochemical defects, including impaired ubiquitin ligase activity and altered oligomerization properties of the CHIP.
    explanation: Similar in vitro defects do not distinguish dominant from recessive inheritance or establish disease penetrance in a heterozygous relative.
  - reference: PMID:31619515
    reference_title: Changes in protein function underlie the disease spectrum in patients with CHIP mutations.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: given the recessive and sometimes compound heterozygous nature of SCAR16, these analyses were performed on a per allele basis.
    explanation: The analysis unit limits interpretation of the domain-phenotype association; its percentages are not patient penetrance estimates.
  - reference: PMID:32713943
    reference_title: 'Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: heterozygous carriers may become symptomatic later
    explanation: The 2020 study reported heterozygous p.Asn65Ser carriers with later onset, while some relatives carrying other recessive alleles remained unaffected; inheritance cannot be assigned from biochemical activity alone.
  variants:
  - name: STUB1 c.633G>A (p.Met211Ile)
    type: missense
    variant_type: single nucleotide variant
    description: Missense allele reported in trans with p.Glu238Ter in two affected siblings. The primary report found segregation and decreased CHIP abundance in mutant-expression cells and patient fibroblasts.
    evidence:
    - reference: url:https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
      reference_title: https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: compound heterozygous variants in STUB1 gene (c.633G >A, p.Met211Ile and c.712G>T, p.Glu238Ter)
      explanation: 'Bettencourt 2015 (PMID:25592071), recovered full text: The report identifies these two segregating alleles in the recessive family. No contemporary ACMG class is assigned here.'
  - name: STUB1 c.712G>T (p.Glu238Ter)
    type: nonsense
    variant_type: single nucleotide variant
    description: Premature stop allele reported in trans with p.Met211Ile in the same family. Truncation and/or nonsense-mediated decay were proposed; patient RNA decay was not demonstrated in the report.
    evidence:
    - reference: url:https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
      reference_title: https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: compound heterozygous variants in STUB1 gene (c.633G >A, p.Met211Ile and c.712G>T, p.Glu238Ter)
      explanation: 'Bettencourt 2015 (PMID:25592071), recovered full text: The report identifies these two segregating alleles in the recessive family. No contemporary ACMG class is assigned here.'
  - name: STUB1 p.Glu28Lys
    type: missense
    variant_type: single nucleotide variant
    description: TPR-domain disease-associated allele. Recombinant Hsc70- and self-ubiquitination were similar to wild type in 2017, with altered proteolytic susceptibility and oligomer distribution.
    evidence:
    - reference: PMID:28396517
      reference_title: In vitro characterization of six STUB1 variants in spinocerebellar ataxia 16 reveals altered structural properties for the encoded CHIP proteins.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: six previously reported pathogenic STUB1 variants (E28K, N65S, K145Q, M211I, S236T, and T246M)
      explanation: Names the disease-associated variant in the 2017 functional study; the description preserves its assay-specific behavior.
    - reference: PMID:25258038
      reference_title: STUB1 mutations in autosomal recessive ataxias - evidence for mutation-specific clinical heterogeneity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: a missense change (c.82G > A, p.Glu28Lys) which was inherited in trans with a nonsense mutation (c.430A > T, p.Lys144Ter)
      explanation: The original family confirms the allele in trans with a truncating variant.
  - name: STUB1 p.Asn65Ser
    type: missense
    variant_type: single nucleotide variant
    description: TPR-domain disease-associated allele with impaired Hsc70 ubiquitination but preserved self-ubiquitination, increased dimerization and resistance to limited proteolysis in 2017.
    evidence:
    - reference: PMID:28396517
      reference_title: In vitro characterization of six STUB1 variants in spinocerebellar ataxia 16 reveals altered structural properties for the encoded CHIP proteins.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: six previously reported pathogenic STUB1 variants (E28K, N65S, K145Q, M211I, S236T, and T246M)
      explanation: Names the disease-associated variant in the 2017 functional study; the description preserves its assay-specific behavior.
    - reference: PMID:25258038
      reference_title: STUB1 mutations in autosomal recessive ataxias - evidence for mutation-specific clinical heterogeneity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: a homozygous missense variant (c.194A > G, p.Asn65Ser) that segregated in three affected siblings
      explanation: Clinical segregation in the original family, distinct from recombinant functional evidence.
  - name: STUB1 p.Lys145Gln
    type: missense
    variant_type: single nucleotide variant
    description: Disease-associated allele with wild-type-like ubiquitination in the 2017 recombinant assays and altered protein structural properties; cellular and other-substrate effects require separate evidence.
    evidence:
    - reference: PMID:28396517
      reference_title: In vitro characterization of six STUB1 variants in spinocerebellar ataxia 16 reveals altered structural properties for the encoded CHIP proteins.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: six previously reported pathogenic STUB1 variants (E28K, N65S, K145Q, M211I, S236T, and T246M)
      explanation: Names the disease-associated variant in the 2017 functional study; the description preserves its assay-specific behavior.
    - reference: PMID:28193273
      reference_title: 'STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: two affected siblings (II.1 and II.4) both carried the mutations p.Lys145Gln and p.Pro243Leu.
      explanation: Clinical segregation with a second allele provides evidence separate from recombinant protein assays.
    - reference: PMID:41851873
      reference_title: A novel STUB1 p.(Gln118*) nonsense variant in compound heterozygosity causes autosomal recessive spinocerebellar ataxia type 16 in a Chinese patient.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: her mother was heterozygous for the c.433 A > C variant.
      explanation: The 2026 patient carried maternal p.Lys145Gln in trans with paternal p.Gln118Ter.
  - name: STUB1 p.Ser236Thr
    type: missense
    variant_type: single nucleotide variant
    description: Disease-associated allele with wild-type-like Hsc70- and self-ubiquitination in 2017 but altered structural stability. The 2013 HEK293 NR2A-degradation assay showed a defect, illustrating substrate- and context-dependent functional results.
    evidence:
    - reference: PMID:28396517
      reference_title: In vitro characterization of six STUB1 variants in spinocerebellar ataxia 16 reveals altered structural properties for the encoded CHIP proteins.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: six previously reported pathogenic STUB1 variants (E28K, N65S, K145Q, M211I, S236T, and T246M)
      explanation: Names the disease-associated variant in the 2017 functional study; the description preserves its assay-specific behavior.
    - reference: PMID:24312598
      reference_title: Identification of CHIP as a novel causative gene for autosomal recessive cerebellar ataxia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: c.621CG (p.Y207X) and c. 707GC (p. S236T)
      explanation: The discovery report pairs p.Ser236Thr with p.Tyr207Ter in family 3.
  - name: STUB1 p.Thr246Met
    type: missense
    variant_type: single nucleotide variant
    description: U-box disease allele associated with ataxia and hypogonadism in a homozygous family. Recombinant experiments show absent Hsc70- and self-ubiquitination and prominent higher-order oligomerization.
    evidence:
    - reference: PMID:28396517
      reference_title: In vitro characterization of six STUB1 variants in spinocerebellar ataxia 16 reveals altered structural properties for the encoded CHIP proteins.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: six previously reported pathogenic STUB1 variants (E28K, N65S, K145Q, M211I, S236T, and T246M)
      explanation: Names the disease-associated variant in the 2017 functional study; the description preserves its assay-specific behavior.
  - name: STUB1 c.430A>T (p.Lys144Ter)
    type: nonsense
    variant_type: single nucleotide variant
    description: Truncating allele confirmed in trans with p.Glu28Lys in a woman with ataxia and hypogonadotropic hypogonadism. The mutant transcript and truncated protein were not detected in patient material, consistent with nonsense-mediated decay; the study did not directly inhibit the decay pathway to establish that mechanism. A 2026 coding-sequence overexpression experiment produced truncated p.Lys144Ter protein; that construct result does not refute the original patient-RNA observation.
    evidence:
    - reference: PMID:25258038
      reference_title: STUB1 mutations in autosomal recessive ataxias - evidence for mutation-specific clinical heterogeneity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: a missense change (c.82G > A, p.Glu28Lys) which was inherited in trans with a nonsense mutation (c.430A > T, p.Lys144Ter)
      explanation: The original patient report establishes the compound-heterozygous pair.
    - reference: PMID:41851873
      reference_title: A novel STUB1 p.(Gln118*) nonsense variant in compound heterozygosity causes autosomal recessive spinocerebellar ataxia type 16 in a Chinese patient.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: the p.(Gln118*) and p.(Lys144*) variants generated truncated proteins
      explanation: Truncated protein was observed after expression-plasmid transfection, not measured in patient tissue.
  - name: STUB1 c.355C>T (p.Arg119Ter)
    type: nonsense
    variant_type: single nucleotide variant
    description: Reported in trans with p.Ile294Phe in a patient with ataxia, severe dementia, pyramidal disease and hypogonadism. Nonsense-mediated decay was predicted rather than directly demonstrated.
    evidence:
    - reference: PMID:28193273
      reference_title: 'STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: one affected individual (II.1) carried the compound heterozygeous mutations p.Arg119* and p.Ile294Phe.
      explanation: The original family study confirms phase by parental testing and describes the associated recessive phenotype.
  - name: STUB1 c.880A>T (p.Ile294Phe)
    type: missense
    variant_type: single nucleotide variant
    description: U-box missense variant confirmed in trans with p.Arg119Ter. The 2017 primary report specifies phenylalanine at residue 294.
    evidence:
    - reference: PMID:28193273
      reference_title: 'STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: one affected individual (II.1) carried the compound heterozygeous mutations p.Arg119* and p.Ile294Phe.
      explanation: The original family study confirms phase by parental testing and describes the associated recessive phenotype.
  - name: STUB1 c.728C>T (p.Pro243Leu)
    type: missense
    variant_type: single nucleotide variant
    description: U-box variant confirmed in trans with p.Lys145Gln in two siblings with ataxia, severe cognitive decline, spasticity and choreoathetosis.
    evidence:
    - reference: PMID:28193273
      reference_title: 'STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: two affected siblings (II.1 and II.4) both carried the mutations p.Lys145Gln and p.Pro243Leu.
      explanation: The original family study confirms phase by parental testing and describes the associated recessive phenotype.
  - name: STUB1 NM_005861.2:c.612+11C>G
    type: intronic variant
    variant_type: single nucleotide variant
    genomic_contexts:
    - intron
    clinical_significance: UNCERTAIN_SIGNIFICANCE
    description: Maternally inherited homozygous intronic variant in a patient with Gordon Holmes features and chromosome-16 regions of absent heterozygosity consistent with maternal uniparental isodisomy. The 2024 online report classified the variant as uncertain despite considering the presentation diagnostic. SpliceAI and MaxEntScan predicted donor-site gain; no patient RNA or functional splice assay was reported. The case was investigated through the observational HSP Genomic Sequencing Initiative (NCT05354622); study ascertainment does not establish this variant as causal.
    evidence:
    - reference: url:https://www.def-lab.org/wp-content/uploads/2024/12/2024-Agianda-MDCP.pdf
      reference_title: https://www.def-lab.org/wp-content/uploads/2024/12/2024-Agianda-MDCP.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: This variant was classi ﬁed as a variant of uncertain signi ﬁcance
      explanation: 'Agianda et al. (PMID:39728009), author-hosted full text: The original authors explicitly retain uncertain significance; the phenotype does not replace molecular validation of splicing.'
    - reference: url:https://www.def-lab.org/wp-content/uploads/2024/12/2024-Agianda-MDCP.pdf
      reference_title: https://www.def-lab.org/wp-content/uploads/2024/12/2024-Agianda-MDCP.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: through the HSP Genomic Sequencing Initiative (NCT05354622)
      explanation: 'Agianda et al. (PMID:39728009), full text: The reported UPD/VUS case was identified through this observational study.'
  - name: STUB1 NM_005861.4:c.352C>T (p.Gln118Ter)
    type: nonsense
    variant_type: single nucleotide variant
    clinical_significance: PATHOGENIC
    description: Paternally inherited truncating allele in trans with maternal p.Lys145Gln in a woman with slowly progressive ataxia beginning at age 27. Classified as pathogenic in the 2026 report. Overexpression constructs produced truncated protein and reduced Hsc70 polyubiquitination; expression-vector RNA findings do not establish escape from nonsense-mediated decay in patient tissue.
    evidence:
    - reference: PMID:41851873
      reference_title: A novel STUB1 p.(Gln118*) nonsense variant in compound heterozygosity causes autosomal recessive spinocerebellar ataxia type 16 in a Chinese patient.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: the c.352 C > T, p.(Gln118*) variant of STUB1 was classified as pathogenic
      explanation: The 2026 authors classified this allele as pathogenic using their clinical, segregation and functional evidence.
  - name: STUB1 c.721C>T (p.Arg241Trp)
    type: missense
    variant_type: single nucleotide variant
    description: Reported in trans with p.Lys145Gln in a Taiwanese SCAR16 family.
    evidence:
    - reference: PMID:32367277
      reference_title: Clinical and Genetic Characterization of Autosomal Recessive Spinocerebellar Ataxia Type 16 (SCAR16) in Taiwan.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Among them, STUB1 p.R241W and p.C232G were novel mutations.
      explanation: The primary clinical abstract reports the two phased allele pairs; no contemporary ACMG classification is inferred.
  - name: STUB1 c.694T>G (p.Cys232Gly)
    type: missense
    variant_type: single nucleotide variant
    description: Reported in trans with p.Lys145Gln in a second Taiwanese SCAR16 family.
    evidence:
    - reference: PMID:32367277
      reference_title: Clinical and Genetic Characterization of Autosomal Recessive Spinocerebellar Ataxia Type 16 (SCAR16) in Taiwan.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Among them, STUB1 p.R241W and p.C232G were novel mutations.
      explanation: The primary clinical abstract reports the two phased allele pairs; no contemporary ACMG classification is inferred.
  - name: STUB1 p.Leu165Phe
    type: missense
    variant_type: single nucleotide variant
    description: Homozygous founding allele in four affected siblings; their parents and an unaffected sibling were heterozygous.
    evidence:
    - reference: PMID:24312598
      reference_title: Identification of CHIP as a novel causative gene for autosomal recessive cerebellar ataxia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: the patients (II:1, 2, 3 and 5) were homozygous at c.493CT (p.L165F) of CHIP
      explanation: The original clinical and segregation study reports this allele; no contemporary ACMG classification is inferred.
  - name: STUB1 p.Asn130Ile
    type: missense
    variant_type: single nucleotide variant
    description: Reported in trans with p.Trp147Cys in the second family of the 2013 discovery study.
    evidence:
    - reference: PMID:24312598
      reference_title: Identification of CHIP as a novel causative gene for autosomal recessive cerebellar ataxia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: c.389AT (p.N130I) and c.441GT (p.W147C)
      explanation: The original clinical and segregation study reports this allele; no contemporary ACMG classification is inferred.
  - name: STUB1 p.Trp147Cys
    type: missense
    variant_type: single nucleotide variant
    description: Reported in trans with p.Asn130Ile in the second discovery family.
    evidence:
    - reference: PMID:24312598
      reference_title: Identification of CHIP as a novel causative gene for autosomal recessive cerebellar ataxia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: c.389AT (p.N130I) and c.441GT (p.W147C)
      explanation: The original clinical and segregation study reports this allele; no contemporary ACMG classification is inferred.
  - name: STUB1 p.Tyr207Ter
    type: nonsense
    variant_type: single nucleotide variant
    description: Reported in trans with p.Ser236Thr in the third discovery family; the truncation removes the U-box domain.
    evidence:
    - reference: PMID:24312598
      reference_title: Identification of CHIP as a novel causative gene for autosomal recessive cerebellar ataxia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: (p.Y207X) mutation encodes a truncated protein without a U-box domain
      explanation: The original clinical and segregation study reports this allele; no contemporary ACMG classification is inferred.
  - name: STUB1 p.Leu231Val
    type: missense
    variant_type: single nucleotide variant
    description: Homozygous allele in Roux et al. 2020 family AAR-030 with Gordon Holmes features. Heterozygous transmitting relatives had no obvious ataxic or cognitive impairment at their reported examinations. A second homozygous ATM p.Glu299Gly VUS was not established as causal.
    evidence:
    - reference: PMID:32713943
      reference_title: 'Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: the homozygous p.L231V STUB1 variant explains the phenotype of ataxia with hypogonadism
      explanation: Table 1 and the recessive subset of Table 2 identify the allele and family. No modern ACMG class or functional assay is inferred.
  - name: STUB1 p.Ala120Val
    type: missense
    variant_type: single nucleotide variant
    description: Reported with p.Met211Thr as a compound-heterozygous pair in family SAL-399-729 in the 2020 series; these biallelic cases must be distinguished from the predominantly heterozygous cohort.
    evidence:
    - reference: PMID:32713943
      reference_title: 'Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: SAL-399–729 – g.681438 C>T c.359 C>T p.A120V c Missense
      explanation: Table 1 and the recessive subset of Table 2 identify the allele and family. No modern ACMG class or functional assay is inferred.
  - name: STUB1 p.Met211Thr
    type: missense
    variant_type: single nucleotide variant
    description: Reported with p.Ala120Val in the biallelic family SAL-399-729. This substitution differs from the p.Met211Ile allele in the 2015 autopsy family.
    evidence:
    - reference: PMID:32713943
      reference_title: 'Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: SAL-399–729 rs1481222863 g.682039 T>C c.632 T>C p.M211T c Missense
      explanation: Table 1 and the recessive subset of Table 2 identify the allele and family. No modern ACMG class or functional assay is inferred.
inheritance:
- name: Autosomal recessive inheritance
  description: SCAR16 usually segregates as an autosomal recessive trait through homozygous or compound heterozygous pathogenic variants. A reported Gordon Holmes case had homozygous STUB1 c.612+11C>G in regions consistent with maternal uniparental isodisomy; the source classified that allele as a VUS, and the predicted splice effect remains unverified.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:24312598
    reference_title: Identification of CHIP as a novel causative gene for autosomal recessive cerebellar ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In a two-generation autosomal recessive cerebellar ataxia family, we mapped a linkage to a minimal candidate region on chromosome 16p13.3
    explanation: Linkage in an autosomal recessive pedigree localizing the disease to the STUB1 locus.
  - reference: PMID:24113144
    reference_title: Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We performed exome sequencing in a family with two of three siblings afflicted with ataxia and hypogonadism and identified a homozygous mutation in STUB1
    explanation: A homozygous variant segregating in affected siblings of unaffected parents is the recessive pattern.
  - reference: url:https://www.def-lab.org/wp-content/uploads/2024/12/2024-Agianda-MDCP.pdf
    reference_title: https://www.def-lab.org/wp-content/uploads/2024/12/2024-Agianda-MDCP.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: absence of heterozygosity on chromosome 16, consistent with UPiD(16)mat, covering a homozygous variant in STUB1.
    explanation: 'Agianda et al. (PMID:39728009), author-hosted full text: The report supports the unusual route to homozygosity but does not establish pathogenicity of the intronic allele.'
prevalence:
- population: German ataxia and spastic paraplegia referral cohort
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: Diagnostic yield within a referral population, not a population prevalence. Three of 167 degenerative ataxia subjects carried biallelic STUB1 variants; none of 133 spastic paraplegia subjects did. Recorded as UNKNOWN measure type because a diagnostic-yield fraction is neither a prevalence nor an incidence, and no population-level estimate for SCAR16 exists in the literature reviewed.
  evidence:
  - reference: PMID:24742043
    reference_title: 'Phenotype and frequency of STUB1 mutations: next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified 3 ataxia patients (3/167 = 1.8%) with 4 novel missense mutations in STUB1
    explanation: The study reports STUB1-related recessive ataxia in 3 of 167 degenerative-ataxia referrals and no STUB1 cases among 133 subjects with predominant spastic paraplegia. These are diagnostic yields in selected cohorts, not a population prevalence.
  - reference: PMID:24742043
    reference_title: 'Phenotype and frequency of STUB1 mutations: next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: STUB1 is rare in subjects with predominant spastic paraplegia (0/133)
    explanation: Records the zero yield in the spastic paraplegia arm of the same screening study.
- population: Taiwanese cerebellar ataxia families
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: 'Diagnostic yield, not a population prevalence: two SCAR16 pedigrees among 512 Taiwanese families screened for cerebellar ataxia.'
  evidence:
  - reference: PMID:32367277
    reference_title: Clinical and Genetic Characterization of Autosomal Recessive Spinocerebellar Ataxia Type 16 (SCAR16) in Taiwan.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: SCAR16 seems to be an uncommon ataxic syndrome, accounting for 0.4% (2/512) of our cohort with cerebellar ataxia.
    explanation: Source of the 0.4% yield in the Taiwanese ataxia cohort.
- population: German and Belgian ataxia index cohorts
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: Diagnostic yield in exome-screened ataxia index subjects, not a population prevalence.
  evidence:
  - reference: PMID:28193273
    reference_title: 'STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified four novel STUB1 mutations in three affected subjects from two index families (frequency 2/87 = 2.3%).
    explanation: Source of the 2.3% yield among ataxia index subjects.
animal_models:
- name: Chip U-box truncation zebrafish
  species: Zebrafish
  genotype: Homozygous stub1 p.Thr255ValfsTer3 U-box truncation
  publication: PMID:34630034
  description: Engineered U-box truncation abolishes detectable Hsc70 ubiquitination in the recombinant assay but retains a mono-self-ubiquitination band. Early development, longevity and breeding were reported as normal. The model captures selected cellular features of CHIP deficiency rather than a patient-specific allele.
  evidence:
  - reference: PMID:34630034
    reference_title: Chip Protein U-Box Domain Truncation Affects Purkinje Neuron Morphology and Leads to Behavioral Changes in Zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Recombinant wild-type zebrafish Chip showed ubiquitin ligase activity highly comparable to human CHIP, while the mutant Chip protein showed impaired ubiquitination of the Hsc70 substrate and Chip itself.
    explanation: Establishes that the fish orthologue is functionally comparable to human CHIP and that the mutant reproduces the ligase defect, which is what makes the model informative for human STUB1 disease.
  modeled_mechanisms:
  - target: Purkinje Cell Degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Purkinje-cell body counts were reduced at 6 and 24 months; cell-body area was reduced at 24 months. Dendritic organization was abnormal, with increased spine counts significant at 6 months only.
    limitations: No gross cerebellar atrophy was demonstrated through 24 months, although absolute cerebellar area was slightly smaller at that age. TUNEL analysis did not confirm cell death. Open-field locomotion and light/dark preference were not significantly altered; increased top-zone exploration in the novel tank is not a demonstrated ataxic motor deficit. The engineered truncation models only part of the human allelic spectrum.
    readouts:
    - name: Purkinje cell body number and size
      target: Purkinje Cell Degeneration
      direction: DECREASED
      interpretation: Purkinje-cell counts were lower at both measured ages; the reduction in cell-body area was significant only at 24 months.
      evidence:
      - reference: PMID:34630034
        reference_title: Chip Protein U-Box Domain Truncation Affects Purkinje Neuron Morphology and Leads to Behavioral Changes in Zebrafish.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: these fish displayed reduced numbers and sizes of Purkinje cell bodies and abnormal organization of Purkinje cell dendrites
        explanation: Reports the Purkinje cell measurement behind this readout.
    evidence:
    - reference: PMID:34630034
      reference_title: Chip Protein U-Box Domain Truncation Affects Purkinje Neuron Morphology and Leads to Behavioral Changes in Zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: truncation of the Chip U-box domain leads to impaired ubiquitin ligase activity and behavioral and anatomical changes in zebrafish, illustrating the potential of zebrafish to study STUB1-mediated diseases
      explanation: The authors' own statement that the model is informative for STUB1-mediated disease.
  - target: Failure of Chaperone-Assisted Protein Quality Control
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Whole-brain 26S proteasome activity was reduced at 24 months, but not at 6 months, when Purkinje-cell counts were already reduced. The timing does not establish this measured decline as the initiating cause of cell loss.
    limitations: A11 oligomer abundance and immunohistochemical NR2A, Hsp70 and ataxin-3 readouts were not significantly increased. This model does not establish generalized aggregate accumulation.
    readouts:
    - name: Brain 26S proteasome activity
      target: Failure of Chaperone-Assisted Protein Quality Control
      direction: DECREASED
      interpretation: Whole-brain 26S proteasome activity was reduced at 24 months, but not at 6 months, when Purkinje-cell counts were already reduced. The timing does not establish this measured decline as the initiating cause of cell loss.
      evidence:
      - reference: PMID:34630034
        reference_title: Chip Protein U-Box Domain Truncation Affects Purkinje Neuron Morphology and Leads to Behavioral Changes in Zebrafish.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Mutant fish also had decreased total 26S proteasome activity in the brain
        explanation: Reports the proteasome activity measurement.
    evidence:
    - reference: PMID:34630034
      reference_title: Chip Protein U-Box Domain Truncation Affects Purkinje Neuron Morphology and Leads to Behavioral Changes in Zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: No differences were evident in the proteasome activity of U-box–/– compared to the wild-type fish brains at a 6-month time point.
      explanation: The significant reduction emerged at 24 months; earlier Purkinje-cell count abnormalities cannot be attributed directly to the measured late proteasome decline.
    - reference: PMID:34630034
      reference_title: Chip Protein U-Box Domain Truncation Affects Purkinje Neuron Morphology and Leads to Behavioral Changes in Zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: However, these effects did not result in an apparent accumulation of specific oligomers nor differences in the expression of three known CHIP protein substrates.
      explanation: Negative protein-accumulation readouts constrain the mechanistic interpretation.
- name: CHIP T246M knock-in mouse
  species: Mouse
  genotype: Homozygous Stub1 p.Thr247Met knock-in, orthologous to human p.Thr246Met
  publication: PMID:30222779
  description: Endogenous knock-in of the rodent residue corresponding to the human p.Thr246Met SCAR16 allele. The paper calls the model T246M while its mouse-locus methods identify T247M. Young mice initially learn the rotarod task, then develop progressive motor impairment, Purkinje-cell loss, reduced brain mass and cognitive readout abnormalities.
  evidence:
  - reference: PMID:30222779
    reference_title: Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: To establish preclinical models of SCAR16, we engineered T246M at the endogenous locus in both mice and rats.
    explanation: Establishes the models as purpose-built SCAR16 models carrying the patient allele at its native locus.
  modeled_mechanisms:
  - target: Progressive Cerebellar Ataxia
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Rotarod performance declines from about 30 weeks, with progressive abnormalities in a composite ataxia score.
    evidence:
    - reference: PMID:30222779
      reference_title: Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: mice decreased starting around 30 weeks of age
      explanation: The mouse-specific results describe later motor decline after initially preserved rotarod learning.
    readouts:
    - name: Rotarod performance with age
      target: Progressive Cerebellar Ataxia
      direction: DECREASED
      interpretation: Age-dependent loss of motor performance in homozygous knock-in mice.
      evidence:
      - reference: PMID:30222779
        reference_title: Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: young M246/M246 mice performed similarly to T246/T246 and T246/M246 mice
        explanation: Initial learning was preserved; the following sentence describes deterioration beginning around 30 weeks.
    limitations: Models one allele. Its progression differs from the severe early impairment of Stub1-null mice.
  - target: Purkinje Cell Degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Aged knock-in mice show reduced CHIP staining and loss of calbindin-positive Purkinje cells; Figure 5H examines 52-week-old animals.
    evidence:
    - reference: PMID:30222779
      reference_title: Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: we observed a decrease in CHIP reactivity in Purkinje cells as well as a loss in calbindin-positive cells
      explanation: The mouse-specific tissue results document the cellular lesion.
  - target: Cognitive Decline
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Contextual and cue-dependent fear conditioning are impaired. Older mice also develop reduced prepulse inhibition despite preserved acoustic startle amplitude.
    evidence:
    - reference: PMID:30222779
      reference_title: Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: M246/M246 mice had impairments in the conditioned fear procedure, both in contextual and cue-dependent learning
      explanation: The paper assigns conditioned-fear testing to mice, distinguishing it from the rat water-maze assay.
    readouts:
    - name: Conditioned freezing
      target: Cognitive Decline
      direction: DECREASED
      interpretation: Reduced learned freezing is a behavioral correlate of impaired associative learning.
      evidence:
      - reference: PMID:30222779
        reference_title: Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: they did not increase their freezing time
        explanation: The contextual and cue tests, including later retention tests, showed impaired learned freezing.
    limitations: These behavioral tasks do not establish the full human dementia phenotype; abnormal activity can affect behavioral readouts.
- name: CHIP T246M-equivalent knock-in rat
  species: Rat
  genotype: Homozygous endogenous Stub1 knock-in orthologous to human p.Thr246Met
  publication: PMID:30222779
  description: CRISPR/Cas9-engineered Sprague Dawley rats carrying the ortholog of the human p.Thr246Met allele. The paper calls the model T246M and labels the targeting vector T247M. Rats show reduced CHIP abundance, Purkinje-cell degeneration, motor impairment, altered gait, learning deficits, lower body weight and reduced survival.
  evidence:
  - reference: PMID:30222779
    reference_title: Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: we developed a rat model also harboring the same endogenous CHIP-T246M mutation.
    explanation: The full scientific body reports rat-specific outcomes and the methods describe the CRISPR/Cas9 line.
  modeled_mechanisms:
  - target: Reduced CHIP Protein Abundance
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: CHIP protein abundance is reduced in cerebellum, whole brain and testes and declines further with age; reduced tissue abundance is the modeled component.
    evidence:
    - reference: PMID:30222779
      reference_title: Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: steady-state levels of CHIP-T246M expression are 40% lower
      explanation: Rat tissue measurements document reduced abundance, not direct visualization of intracellular oligomers.
  - target: Purkinje Cell Degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: At 32 weeks, rat cerebellar sections show reduced calbindin staining and fewer Purkinje cells.
    evidence:
    - reference: PMID:30222779
      reference_title: Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: identified Purkinje cell degeneration, evidenced by decreased calbindin staining
      explanation: The rat-specific results and Figure 5D-E document the cerebellar cellular phenotype.
  - target: Progressive Cerebellar Ataxia
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Rat rotarod impairment is present from 12 weeks, persists during longitudinal follow-up, and accompanies age-dependent gait abnormalities.
    evidence:
    - reference: PMID:30222779
      reference_title: Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: The loss in rotatrod performance was also accompanied by changes in gait
      explanation: The text and Figure 7A-E assign these motor and gait measurements to rats; one sentence mistakenly calls them mice.
    limitations: This allele-specific rodent model does not reproduce every endocrine or neurological manifestation of human SCAR16.
  - target: Cognitive Decline
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Young and adult rats show impaired Morris water-maze learning and reduced occupancy of the former platform zone during memory testing.
    evidence:
    - reference: PMID:30222779
      reference_title: Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: the conditioned fear response test, in rats and mice, respectively.
      explanation: The preceding clause names the Morris water maze, and the subsequent results assign it to rats. The reported decrease in escape latency conflicts with the interpretation of impaired learning, so that directional latency claim is not adopted.
    limitations: Spatial-learning and probe-trial behavior are proxies for cognitive function, not evidence of human-like dementia.
- name: Stub1-null mouse comparator
  species: Mouse
  genotype: Homozygous Stub1 knockout
  publication: PMID:30222779
  description: Comparator representing complete loss of CHIP rather than a patient missense allele. Null mice are already ataxic at weaning and fail initial rotarod learning; the knock-in mice instead show greater subsequent progression.
  evidence:
  - reference: PMID:30222779
    reference_title: Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: CHIP−/− mice were already ataxic at weaning
    explanation: The study directly contrasts the onset and progression of the null and knock-in lines.
  modeled_mechanisms:
  - target: Progressive Cerebellar Ataxia
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Severe early ataxia and absent initial rotarod learning model motor dysfunction from complete CHIP loss.
    evidence:
    - reference: PMID:30222779
      reference_title: Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: had a complete lack of learning of rotarod behavior
      explanation: The null mice were impaired during initial training, unlike young knock-in mice.
    limitations: The severe baseline phenotype and slower subsequent score progression differ from the knock-in model and do not establish equivalence to all SCAR16 alleles.
- name: chn-1 loss-of-function worm mitophagy reporters
  species: Caenorhabditis elegans
  genotype: chn-1(by155) and chn-1(tm2692), with neuronal reporters; pink-1 and pdr-1 double-mutant comparisons
  publication: PMID:39117117
  description: Adult-day-one worms with loss of the CHIP orthologue were assessed with neuronal mitochondrial and lysosomal-delivery reporters. Increased basal neuronal mitophagy in chn-1(by155) was reduced by loss of pink-1 or pdr-1. The separate disease-analogue knock-ins in the paper model dominant SCA48 variants and are not represented as recessive patient-allele models here.
  evidence:
  - reference: url:https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf
    reference_title: https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: the increase in neuronal mitophagy observed in chn-1(by155) worms is dependent on both PINK1 and Parkin.
    explanation: 'Earnshaw et al. 2024 (PMID:39117117), recovered full text: Double-mutant comparisons establish pathway dependence in the worm loss-of-function model.'
  modeled_mechanisms:
  - target: Excess PINK1/Parkin-Mediated Mitophagy
    relationship: PERTURBS
    fidelity: LOW
    model_scale: CELLULAR
    description: Loss of chn-1 increases basal neuronal mitochondrial delivery to lysosomes.
    limitations: Gene-level perturbation in worm neurons, without human Purkinje cells or a recessive patient allele. No causal link from this readout to human SCAR16 neurodegeneration was demonstrated.
    evidence:
    - reference: url:https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf
      reference_title: https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: worms, indicating that mitophagy is elevated in worms with loss of CHIP compared to WT controls
      explanation: 'Earnshaw et al. 2024 (PMID:39117117), recovered full text: The pH-sensitive mitochondrial reporter supports increased lysosomal delivery in the worm model.'
- name: CHIP T246M rat PDE9A intervention cohorts
  species: Rat
  genotype: Homozygous Stub1 T246M model as designated by the study
  publication: PMID:39806097
  description: The 2025 follow-up used homozygous mutant male rats, wild-type littermates, BAY 73-6691 treatment and AAV-CHIP supplementation; the AAV experiment also used an empty-vector control. Outcomes included rotarod, beam traversal, gait, water maze, Purkinje-cell histology, mitochondrial electron microscopy and tissue molecular assays. Behavioral cohorts differ in endpoint age and sample size. Higher cell density at the endpoint is not a longitudinal demonstration of neuronal regeneration.
  evidence:
  - reference: PMID:39806097
    reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Hom(6M+) rats treated with Bay 73-6691 performed similarly to age-matched wild-type and presymptomatic Hom(6M-) rats, which was consistent with improved motor function
    explanation: In homozygous mutant male rats, PDE9A inhibition improved rotarod and beam performance; no human treatment was studied.
  - reference: PMID:39806097
    reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: behavioural observations revealed improved balance, coordination and gait in the homozygous mutant rats
    explanation: AAV-mediated CHIP supplementation improved motor and memory readouts in mutant rats, with an empty-vector cohort in the genetic-intervention experiment.
  modeled_mechanisms:
  - target: PDE9A Accumulation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Increased PDE9A protein accompanies reduced CHIP in mutant cerebellar and hippocampal tissue.
    limitations: Single homozygous rat allele model. The intervention results are preclinical and do not demonstrate the same mechanism in human patient tissue.
    evidence:
    - reference: PMID:39806097
      reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: the levels of CHIP, cGMP, PKG1 and PKG2 were diminished in the Hom group, and the PDE9A level was increased
      explanation: Rat cerebellar and hippocampal measurements include cGMP ELISA and protein assays. These establish the model state; they are not patient biomarker measurements.
    readouts:
    - name: PDE9A protein abundance
      target: PDE9A Accumulation
      direction: INCREASED
      interpretation: Increased PDE9A protein accompanies reduced CHIP in mutant cerebellar and hippocampal tissue.
      evidence:
      - reference: PMID:39806097
        reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: the levels of CHIP, cGMP, PKG1 and PKG2 were diminished in the Hom group, and the PDE9A level was increased
        explanation: Rat cerebellar and hippocampal measurements include cGMP ELISA and protein assays. These establish the model state; they are not patient biomarker measurements.
  - target: Reduced cGMP Availability
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Tissue cGMP concentrations are reduced in mutant rats and improve after treatment.
    limitations: Single homozygous rat allele model. The intervention results are preclinical and do not demonstrate the same mechanism in human patient tissue.
    evidence:
    - reference: PMID:39806097
      reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: the levels of CHIP, cGMP, PKG1 and PKG2 were diminished in the Hom group, and the PDE9A level was increased
      explanation: Rat cerebellar and hippocampal measurements include cGMP ELISA and protein assays. These establish the model state; they are not patient biomarker measurements.
    readouts:
    - name: Tissue cGMP concentration
      target: Reduced cGMP Availability
      direction: DECREASED
      interpretation: Tissue cGMP concentrations are reduced in mutant rats and improve after treatment.
      evidence:
      - reference: PMID:39806097
        reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: the levels of CHIP, cGMP, PKG1 and PKG2 were diminished in the Hom group, and the PDE9A level was increased
        explanation: Rat cerebellar and hippocampal measurements include cGMP ELISA and protein assays. These establish the model state; they are not patient biomarker measurements.
  - target: Mitochondrial Structural Injury
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Mitochondrial ultrastructural injury improves after BAY 73-6691 or AAV-CHIP treatment.
    limitations: Single homozygous rat allele model. The intervention results are preclinical and do not demonstrate the same mechanism in human patient tissue.
    evidence:
    - reference: PMID:39806097
      reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Treatment with Bay 73-6691 or AAV-CHIP resulted in a reduction in scores, indicating mitigated mitochondrial damage and morphological improvements in the mutated rats
      explanation: Electron microscopy and Flameng scoring establish mitochondrial structural injury and its improvement in the treated rat cohorts. Static morphology and marker levels do not directly measure mitophagic flux.
    readouts:
    - name: Mitochondrial injury score
      target: Mitochondrial Structural Injury
      direction: INCREASED
      interpretation: Mitochondrial ultrastructural injury improves after BAY 73-6691 or AAV-CHIP treatment.
      evidence:
      - reference: PMID:39806097
        reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Treatment with Bay 73-6691 or AAV-CHIP resulted in a reduction in scores, indicating mitigated mitochondrial damage and morphological improvements in the mutated rats
        explanation: Electron microscopy and Flameng scoring establish mitochondrial structural injury and its improvement in the treated rat cohorts. Static morphology and marker levels do not directly measure mitophagic flux.
experimental_models:
- name: SCAR16 patient primary fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: Primary skin fibroblasts from three SCAR16 patients tested for heat-shock response induction and recovery. The corresponding patient-derived cortical neurons show a different response.
  publication: PMID:33097556
  evidence:
  - reference: PMID:33097556
    reference_title: CHIP mutations affect the heat shock response differently in human fibroblasts and iPSC-derived neurons.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: we investigated the heat shock response (HSR) in primary fibroblasts of three SCAR16 patients
    explanation: Establishes that the model is built from SCAR16 patient material rather than from an unrelated CHIP-deficient line.
  modeled_mechanisms:
  - target: Failure of Chaperone-Assisted Protein Quality Control
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: Patient fibroblasts show impaired heat-shock response induction and recovery, a cellular readout of disturbed proteostasis.
    limitations: Fibroblast is not the disease target tissue, and the same study's patient neurons do not reproduce this defect, so the fibroblast phenotype cannot be read as the neuropathological mechanism. Fidelity is LOW for that reason, not because the measurement is unreliable.
    readouts:
    - name: Heat shock response induction and recovery
      target: Failure of Chaperone-Assisted Protein Quality Control
      direction: DECREASED
      interpretation: Patient-cell readout of disturbed proteostasis.
      evidence:
      - reference: PMID:33097556
        reference_title: CHIP mutations affect the heat shock response differently in human fibroblasts and iPSC-derived neurons.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: We found impaired HSR induction and recovery compared to healthy controls.
        explanation: Reports the heat-shock response measurement in patient fibroblasts.
- name: SCAR16 patient iPSC-derived cortical neurons
  experimental_model_type: IPSC_DERIVED_MODEL
  description: Cortical neurons differentiated from three SCAR16 patient iPSC lines, compared with control lines and an isogenic STUB1 knockout. The day-36 neurons expressed cortical-layer markers and most closely resembled fetal neocortex at postconception week 16. They model a neuronal context but do not establish the response of mature cerebellar Purkinje cells.
  publication: PMID:33097556
  evidence:
  - reference: PMID:33097556
    reference_title: CHIP mutations affect the heat shock response differently in human fibroblasts and iPSC-derived neurons.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: we next investigated the HSR in cortical neurons (CNs) derived from induced pluripotent stem cells of SCAR16 patients
    explanation: Establishes the neuronal model as patient-derived and as the cell type the study treats as disease-relevant.
  - reference: PMID:33097556
    reference_title: CHIP mutations affect the heat shock response differently in human fibroblasts and iPSC-derived neurons.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The better stress coping of CNs could be a result of the immaturity of the CNs
    explanation: The authors identify neuronal immaturity as a possible explanation for the apparent heat-stress resistance.
  modeled_mechanisms:
  - target: Failure of Chaperone-Assisted Protein Quality Control
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Proteomic enrichment patterns were consistent with altered protein folding and oxidative-stress responses in patient cortical neurons. These are proteomic inferences rather than direct measurements of protein-refolding capacity or reactive oxygen species.
    limitations: Immature cortical neurons rather than mature Purkinje cells. High basal HSP70 and culture conditions may limit the heat-shock response. Patient and knockout neurons did not reproduce the fibroblast HSR defect; proteomic pathway enrichment does not itself demonstrate defective refolding or elevated reactive oxygen species.
    readouts:
    - name: Proteomic enrichment of protein-folding and oxidative-stress pathways
      target: Failure of Chaperone-Assisted Protein Quality Control
      direction: ALTERED
      interpretation: Protein-abundance and pathway-enrichment differences support altered proteostasis responses; no direct refolding or ROS assay is represented by this readout.
      evidence:
      - reference: PMID:33097556
        reference_title: CHIP mutations affect the heat shock response differently in human fibroblasts and iPSC-derived neurons.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Proteomic analysis of CNs showed dysfunctional protein (re)folding and higher basal oxidative stress levels in patients.
        explanation: The abstract summarizes the authors' interpretation of proteomic differences. The full-text results establish protein-abundance and enrichment patterns, not direct functional refolding or ROS measurements.
    evidence:
    - reference: PMID:33097556
      reference_title: CHIP mutations affect the heat shock response differently in human fibroblasts and iPSC-derived neurons.
      supports: REFUTE
      evidence_source: IN_VITRO
      snippet: Our results question the role of impaired HSR in SCAR16 neuropathology and highlight the need for careful selection of proper cell types for modeling human diseases.
      explanation: The authors question impaired neuronal HSR as the explanation for disease; the model link is limited to proteomic differences and does not establish mature Purkinje-cell behavior.
- name: SCAR16 p.Met211Ile/p.Glu238Ter patient fibroblasts under proteasome stress
  experimental_model_type: PRIMARY_CELL_CULTURE
  publication: PMID:25259530
  description: Skin fibroblasts from one affected member of a Spanish family with compound heterozygous p.Met211Ile/p.Glu238Ter STUB1 variants, studied alongside three age- and sex-matched control donors. Epoxomicin challenge and trehalose treatment interrogated cell survival, oxidative stress and protein clearance.
  evidence:
  - reference: PMID:25259530
    reference_title: Trehalose improves human fibroblast deficits in a new CHIP-mutation related ataxia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The patient's fibroblasts with a new form of hereditary ataxia, related to STUB1 gene (CHIP) mutations, and three age and sex-matched controls were treated with epoxomicin and trehalose.
    explanation: Defines the patient-derived model and comparator donors.
  modeled_mechanisms:
  - target: Failure of Chaperone-Assisted Protein Quality Control
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: Patient fibroblasts showed stress-associated cell injury, protein ubiquitination and autophagy abnormalities, with improvement in several readouts after trehalose.
    limitations: One patient, non-neuronal tissue and pharmacological proteasome inhibition. Culture replicates are pseudoreplicates, not independent patients. No valid patient-versus-control statistical comparison or demonstrated clinical efficacy; improved mutant CHIP ligase function was not established.
    readouts:
    - name: Epoxomicin-associated apoptosis and trehalose response
      target: Failure of Chaperone-Assisted Protein Quality Control
      direction: ALTERED
      interpretation: Cleaved-caspase-3 staining measures cellular injury under proteasome stress; trehalose-associated rescue does not establish a neuronal treatment effect.
      evidence:
      - reference: PMID:25259530
        reference_title: Trehalose improves human fibroblast deficits in a new CHIP-mutation related ataxia.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Additionally, treatment with epoxomicin produced a dose-dependent increase in the number of cleaved caspase-3 positive cells.
        explanation: Direct cellular apoptosis readout under the experimental proteasome challenge.
- name: Recombinant CHIP disease-variant biochemistry
  experimental_model_type: OTHER
  publication: PMID:28396517
  description: E. coli-expressed wild-type and six disease-associated CHIP proteins tested for Hsc70- and self-ubiquitination, limited trypsin proteolysis, oligomerization and circular-dichroism unfolding. Several structural assays used MBP fusion proteins.
  evidence:
  - reference: PMID:28396517
    reference_title: In vitro characterization of six STUB1 variants in spinocerebellar ataxia 16 reveals altered structural properties for the encoded CHIP proteins.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: six previously reported pathogenic STUB1 variants (E28K, N65S, K145Q, M211I, S236T, and T246M) were expressed as recombinant proteins
    explanation: Defines the experimental allele panel.
  modeled_mechanisms:
  - target: Loss of CHIP E3 Ubiquitin Ligase Activity
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Reproduces substrate-ubiquitination defects for N65S and T246M, while four other variants retain wild-type-like activity in these assays.
    limitations: Purified proteins and selected substrates do not reproduce neuronal protein abundance or all CHIP clients. MBP may influence folding and oligomerization.
    readouts:
    - name: Hsc70 ubiquitination
      direction: ALTERED
      target: Loss of CHIP E3 Ubiquitin Ligase Activity
      interpretation: The catalytic phenotype differs by allele and substrate.
      evidence:
      - reference: PMID:28396517
        reference_title: In vitro characterization of six STUB1 variants in spinocerebellar ataxia 16 reveals altered structural properties for the encoded CHIP proteins.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: N65S and T246M displayed impaired Hsc70-ubiquitination activity for both MBP-fusion and MBP-free forms.
        explanation: Direct assay result for two variants; it is not generalized to the whole panel.
- name: STUB1 truncation constructs in SH-SY5Y and HEK293T cells
  experimental_model_type: CELL_LINE
  publication: PMID:41851873
  description: Transient overexpression of wild-type, p.Gln118Ter, p.Lys144Ter and p.Lys145Gln coding-sequence constructs in SH-SY5Y cells assessed transcript and protein abundance. HEK293T cotransfection with Hsc70 and tagged ubiquitin assessed Hsc70 polyubiquitination for p.Gln118Ter and p.Lys145Gln. These are expression-construct assays, not patient-derived neurons.
  modeled_mechanisms:
  - target: Loss of CHIP E3 Ubiquitin Ligase Activity
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: The p.Gln118Ter construct produced truncated CHIP with reduced Hsc70 polyubiquitination.
    limitations: Overexpression does not reproduce endogenous allelic dosage or establish patient-tissue transcript stability.
    evidence:
    - reference: PMID:41851873
      reference_title: A novel STUB1 p.(Gln118*) nonsense variant in compound heterozygosity causes autosomal recessive spinocerebellar ataxia type 16 in a Chinese patient.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: this truncation mutant exhibited significantly reduced ubiquitination activity toward Hsc70
      explanation: The cellular ubiquitination assay supplies functional evidence for the truncation.
  evidence:
  - reference: PMID:41851873
    reference_title: A novel STUB1 p.(Gln118*) nonsense variant in compound heterozygosity causes autosomal recessive spinocerebellar ataxia type 16 in a Chinese patient.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Cells were harvested 48 h post-transfection for RNA level and protein level analysis.
    explanation: The experimental methods identify the expression-plasmid system and assay timing.
- name: CHIP-perturbed U2OS Parkin mitophagy reporter cells
  experimental_model_type: CELL_LINE
  publication: PMID:39117117
  description: U2OS osteosarcoma cells with stable GFP-Parkin and inducible mitochondrial mKeima were subjected to STUB1 knockdown or CHIP overexpression and CCCP stress. Parkin recruitment, PINK1 abundance and pH-sensitive mitochondrial reporter delivery to lysosomes were measured. U2OS cells lack detectable endogenous Parkin in this system.
  modeled_mechanisms:
  - target: Excess PINK1/Parkin-Mediated Mitophagy
    relationship: PERTURBS
    fidelity: LOW
    model_scale: CELLULAR
    description: CHIP knockdown increases stress-induced mitophagy; wild-type CHIP overexpression suppresses it.
    limitations: Engineered non-neuronal cells under acute chemical stress, without a recessive patient genotype. SCA48-variant overexpression experiments in the same paper do not establish SCAR16-specific function.
    readouts:
    - name: mt-Keima mitophagy-positive cells after CHIP knockdown and CCCP
      target: Excess PINK1/Parkin-Mediated Mitophagy
      direction: INCREASED
      interpretation: Greater mitochondrial reporter exposure to the acidic lysosomal environment.
      evidence:
      - reference: url:https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf
        reference_title: https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf
        supports: SUPPORT
        directness: INDIRECT
        evidence_source: IN_VITRO
        snippet: CHIP knockdown significantly increased the percentage of cells undergoing mitophagy
        explanation: 'Earnshaw et al. 2024 (PMID:39117117), recovered full text: Measured by flow cytometry in the engineered U2OS reporter system after CCCP.'
    evidence:
    - reference: url:https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf
      reference_title: https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: U2OS cells are specifically reliant on the PINK1/Parkin pathway for mitophagy
      explanation: 'Earnshaw et al. 2024 (PMID:39117117), recovered full text: The next sentences specify the need for added Parkin, limiting the model to the engineered pathway.'
  evidence:
  - reference: url:https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf
    reference_title: https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: U2OS cells stably expressing GFP-Parkin or both GFP-Parkin and mito-mKeima
    explanation: 'Earnshaw et al. 2024 (PMID:39117117), recovered full text: The methods identify the reporter cell systems.'
- name: SCAR16 AX71 and AX29 fibroblast PKA-signaling assays
  experimental_model_type: PRIMARY_CELL_CULTURE
  publication: PMID:31189917
  description: Primary skin fibroblasts from two distinct SCAR16 patients compared with healthy-volunteer cells. Forskolin stimulation and H89 inhibition probe the dynamic PKA-CREB response; AX71 was assessed by immunostaining and AX29 by immunoblotting.
  evidence:
  - reference: PMID:31189917
    reference_title: Feedback inhibition of cAMP effector signaling by a chaperone-assisted ubiquitin system.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: STUB1 mutations, like CHIP downregulation, increased basal levels of phosphoCREB-positive nuclei that could not be further induced by FSK.
    explanation: Increased basal CREB phosphorylation and blunted further induction by forskolin model defective signaling attenuation.
  modeled_mechanisms:
  - target: Elevated Basal PKA-CREB Signaling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Increased basal CREB phosphorylation and blunted further induction by forskolin model defective signaling attenuation.
    limitations: Patient-derived non-neuronal cells; variant identities are not specified in this paper. The experiments do not establish human neuronal pathology, endocrine causation or treatment benefit.
    evidence:
    - reference: PMID:31189917
      reference_title: Feedback inhibition of cAMP effector signaling by a chaperone-assisted ubiquitin system.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: STUB1 mutations, like CHIP downregulation, increased basal levels of phosphoCREB-positive nuclei that could not be further induced by FSK.
      explanation: Increased basal CREB phosphorylation and blunted further induction by forskolin model defective signaling attenuation.
    readouts:
    - name: Basal CREB phosphorylation
      target: Elevated Basal PKA-CREB Signaling
      direction: INCREASED
      interpretation: Increased basal CREB phosphorylation and blunted further induction by forskolin model defective signaling attenuation.
      evidence:
      - reference: PMID:31189917
        reference_title: Feedback inhibition of cAMP effector signaling by a chaperone-assisted ubiquitin system.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: STUB1 mutations, like CHIP downregulation, increased basal levels of phosphoCREB-positive nuclei that could not be further induced by FSK.
        explanation: Increased basal CREB phosphorylation and blunted further induction by forskolin model defective signaling attenuation.
- name: SCAR16 AX71 fibroblast cilium-resorption assay
  experimental_model_type: PRIMARY_CELL_CULTURE
  publication: PMID:29581457
  description: Serum-starved primary SCAR16 AX71 fibroblasts and control BJ cells were exposed to forskolin. Acetylated-tubulin staining quantified ciliation; NEK10 siRNA tested pathway dependence.
  evidence:
  - reference: PMID:29581457
    reference_title: Counterregulation of cAMP-directed kinase activities controls ciliogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: no major effects of FSK stimulation on cilia were evident in SCAR16 fibroblasts.
    explanation: Cilia persist after forskolin in the patient-cell assay, whereas control cells undergo resorption.
  modeled_mechanisms:
  - target: Impaired cAMP-Induced Cilium Resorption
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Cilia persist after forskolin in the patient-cell assay, whereas control cells undergo resorption.
    limitations: Non-neuronal model with a culture-condition-dependent effect; the paper does not establish that impaired cilium resorption causes SCAR16 symptoms. The separate medaka experiment perturbs NEK10 rather than STUB1 and is not a SCAR16 animal model.
    evidence:
    - reference: PMID:29581457
      reference_title: Counterregulation of cAMP-directed kinase activities controls ciliogenesis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: no major effects of FSK stimulation on cilia were evident in SCAR16 fibroblasts.
      explanation: Cilia persist after forskolin in the patient-cell assay, whereas control cells undergo resorption.
    readouts:
    - name: Forskolin-induced cilium resorption
      target: Impaired cAMP-Induced Cilium Resorption
      direction: DECREASED
      interpretation: Cilia persist after forskolin in the patient-cell assay, whereas control cells undergo resorption.
      evidence:
      - reference: PMID:29581457
        reference_title: Counterregulation of cAMP-directed kinase activities controls ciliogenesis.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: no major effects of FSK stimulation on cilia were evident in SCAR16 fibroblasts.
        explanation: Cilia persist after forskolin in the patient-cell assay, whereas control cells undergo resorption.
- name: HEK293T CHIP-PDE9A ubiquitination and turnover assays
  experimental_model_type: CELL_LINE
  publication: PMID:39806097
  description: Transfected HEK293T cells compare wild-type CHIP, T246M, engineered K30A and domain deletions, alongside PDE9A Lys186 and ubiquitin-linkage mutants. Cycloheximide, bafilomycin and bortezomib distinguish protein turnover and degradation routes. Overexpression and apoptosis assays are not patient-neuron experiments.
  evidence:
  - reference: PMID:39806097
    reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the T246M mutation corroborated the role of CHIP in PDE9A polyubiquitination
    explanation: Expression and domain-mutant experiments support impaired CHIP-dependent ubiquitination of PDE9A; the disease allele is p.Thr246Met, whereas K30A is an engineered control.
  - reference: PMID:39806097
    reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Mutation of PDE9A at K186R disrupted CHIP-mediated ubiquitination, resulting in an increased half-life and overaccumulation of PDE9A in cells
    explanation: Substrate-site mutagenesis connects ubiquitination to PDE9A turnover. Bafilomycin and bortezomib comparisons support autophagic rather than proteasomal degradation of PDE9A in this system.
  modeled_mechanisms:
  - target: PDE9A Accumulation
    relationship: PERTURBS
    fidelity: LOW
    model_scale: MOLECULAR
    description: Substrate-site and CHIP perturbations test the ubiquitination-dependent control of PDE9A abundance.
    limitations: Heterologous overexpression; does not establish physiological stoichiometry or human neuronal injury.
    evidence:
    - reference: PMID:39806097
      reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Mutation of PDE9A at K186R disrupted CHIP-mediated ubiquitination, resulting in an increased half-life and overaccumulation of PDE9A in cells
      explanation: Substrate-site mutagenesis connects ubiquitination to PDE9A turnover. Bafilomycin and bortezomib comparisons support autophagic rather than proteasomal degradation of PDE9A in this system.
- name: HEK293 CHIP-Fbx2 NR2A-turnover reconstitution
  experimental_model_type: CELL_LINE
  publication: PMID:24312598
  description: HEK293 cells coexpressed NR2A, Fbx2 and wild-type CHIP or the five discovery alleles p.Asn130Ile, p.Trp147Cys, p.Leu165Phe, p.Tyr207Ter and p.Ser236Thr. Cycloheximide chase followed NR2A abundance. Wild-type CHIP plus Fbx2 enhanced turnover; either alone did not significantly do so.
  evidence:
  - reference: PMID:24312598
    reference_title: Identification of CHIP as a novel causative gene for autosomal recessive cerebellar ataxia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Coexpression of WT CHIP and Fbx2 significantly increased the degradation of NR2A
    explanation: The combination, rather than CHIP expression alone, enhanced turnover in the reconstructed cellular system.
  modeled_mechanisms:
  - target: Loss of CHIP E3 Ubiquitin Ligase Activity
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Disease variants failed to support the wild-type CHIP/Fbx2 effect on NR2A turnover.
    limitations: Heterologous overexpression of a selected client. This experiment does not measure NMDA currents, demonstrate neuronal excitotoxicity or prove that NR2A accumulation causes SCAR16.
    evidence:
    - reference: PMID:24312598
      reference_title: Identification of CHIP as a novel causative gene for autosomal recessive cerebellar ataxia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: none of the ARCA-associated CHIP mutants effectively promoted the degradation of NR2A
      explanation: This is a substrate-turnover phenotype, not evidence that every mutant lacks all ubiquitin ligase activity.
- name: Temperature-dependent CHIP missense-variant assays
  experimental_model_type: OTHER
  publication: PMID:29317501
  description: Recombinant proteins were assessed for HSP70 ubiquitination, chaperone-peptide binding, free ubiquitin-chain formation, thermal stability and oligomerization; transfected HEK293 cells supplied a separate protein-abundance readout. The study compared physiological and lower assay temperatures.
  evidence:
  - reference: PMID:29317501
    reference_title: Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: most mutant proteins recovered activity when the assays were performed below the mutants' melting temperature
    explanation: The abstract supports temperature-dependent recovery of function; this is not a clinical cooling intervention.
  modeled_mechanisms:
  - target: CHIP Structural Destabilization
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Most variants showed destabilization and soluble oligomer formation; effects varied across assays and alleles.
    limitations: Purified proteins, a chaperone peptide and transient overexpression cannot establish patient neuronal abundance or a clinical therapeutic response.
    evidence:
    - reference: PMID:29317501
      reference_title: Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: This destabilization caused mutation-specific defects in CHIP activity, including increased formation of soluble oligomers, decreased interactions with chaperones, diminished substrate ubiquitination, and reduced steady-state levels in cells.
      explanation: The aggregate biochemical result is explicitly mutation-specific.
- name: CARP-dependent CHIP sequestration in HEK293T and N2A cells
  experimental_model_type: CELL_LINE
  publication: PMID:36853170
  description: Transfection, ubiquitination, live imaging and detergent-solubility assays assess CARP effects on CHIP. K30A and H260Q are engineered controls; the disease-variant panel includes N65S, K145Q, M240T, T246M and I294F.
  modeled_mechanisms:
  - target: CARP-Dependent CHIP Aggregate Formation
    relationship: PERTURBS
    fidelity: LOW
    model_scale: CELLULAR
    description: CARP expression promotes CHIP sequestration into insoluble material.
    limitations: Overexpression systems; no patient-neuron validation or therapeutic inhibitor was tested.
    evidence:
    - reference: PMID:36853170
      reference_title: CARPs regulate STUB1 and its pathogenic mutants aggregation kinetics by mono-ubiquitination.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: pathogenic mutants of STUB1 are more prone than the wild-type to CARP2-mediated aggregate assembly.
      explanation: CARP2 modifies mutant CHIP and promotes aggregate assembly in experimental systems; human neuronal causation is untested.
  evidence:
  - reference: PMID:36853170
    reference_title: CARPs regulate STUB1 and its pathogenic mutants aggregation kinetics by mono-ubiquitination.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: CARP2 interacts and mono-ubiquitinates STUB1.
    explanation: Experimental interaction and modification of CHIP by CARP2.
treatments:
- name: Supportive and Symptomatic Care
  description: Management is multidisciplinary symptomatic care for ataxia, dysarthria, dysphagia, pyramidal signs and, where present, endocrine and seizure manifestations. No SCAR16-specific disease-modifying intervention was identified in the September 2026 trial search. Cellular and animal therapeutic candidates remain preclinical.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:33200713
    reference_title: 'C-terminus of Hsp70 Interacting Protein (CHIP) and Neurodegeneration: Lessons from the Bench and Bedside.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: These diseases are all incurable at present, with no available treatments to modify the neurodegenerative process or provide neuroprotection.
    explanation: A CHIP-focused review's framing statement about the neurodegenerative diseases it covers, which include the inherited cerebellar ataxias. It supports the absence of disease-modifying therapy at the class level rather than reporting a SCAR16-specific treatment trial; no such trial was found.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/
    reference_title: Hereditary Ataxia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The goals of supportive care are to maximize function and reduce complications.
    explanation: 'General hereditary-ataxia guidance, extrapolated to SCAR16: Supports multidisciplinary supportive management; this is not a SCAR16-specific efficacy study.'
- name: Physical Therapy and Gait Rehabilitation
  description: Balance exercises, gait training and muscle strengthening, with adaptive mobility devices and home fall-prevention measures. Recommendations are extrapolated from general hereditary-ataxia care.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/
    reference_title: Hereditary Ataxia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: PT (balance exercises, gait training, muscle strengthening) to maintain mobility
    explanation: 'General hereditary-ataxia guidance, extrapolated to SCAR16: Identifies the rehabilitation components and intended functional goal.'
- name: Speech and Language Therapy
  description: Speech-language assessment and therapy for dysarthria, with alternative communication methods when needed. Swallowing and feeding management is addressed separately. This recommendation is extrapolated from general hereditary-ataxia care.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech and language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/
    reference_title: Hereditary Ataxia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Consider alternative communication methods as needed
    explanation: 'General hereditary-ataxia guidance, extrapolated to SCAR16: The dysarthria row recommends speech-language therapy and communication aids.'
- name: Occupational Therapy
  description: Adaptive strategies and equipment to preserve independence in daily activities as limb ataxia progresses.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: occupational therapy
    term:
      id: NCIT:C121351
      label: Occupational Therapy
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/
    reference_title: Hereditary Ataxia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: supportive care by a multidisciplinary team of specialists including neurologists, occupational therapists, physical therapists
    explanation: 'General hereditary-ataxia guidance, extrapolated to SCAR16: Supports occupational therapy and adaptive strategies for daily activities.'
- name: Sex Hormone Replacement Therapy
  description: Individualized endocrine replacement addresses sex-steroid deficiency in patients with hypogonadotropic hypogonadism. In the original homozygous p.Thr246Met sisters, estrogen/progestin supplementation induced menstrual bleeding after three weeks. This endocrine response does not establish neurological benefit or restoration of spontaneous gonadotropin function.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: sex hormone replacement therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
    therapeutic_agent:
    - preferred_term: estrogen preparation (unspecified)
    - preferred_term: progestin preparation (unspecified)
  target_mechanisms:
  - target: Hypothalamic-Pituitary Gonadotropin Deficiency
    description: Replaces the sex steroids that the deficient gonadotropin drive fails to elicit, without acting on the CHIP defect upstream.
- name: Trehalose (Preclinical Patient-Fibroblast Candidate)
  description: Trehalose reduced epoxomicin-associated cell injury and oxidative-stress readouts and increased autophagy-associated readouts in fibroblasts from one SCAR16 patient with p.Met211Ile/p.Glu238Ter variants. The study used three control donors and patient culture pseudoreplicates; patient-versus-control statistical comparisons were not valid. Increased CHIP abundance did not establish restored mutant CHIP function, and the authors did not attribute protection to that increase. This is a cell-culture therapeutic lead, not evidence of clinical efficacy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: trehalose
      term:
        id: CHEBI:27082
        label: trehalose
  target_mechanisms:
  - target: Failure of Chaperone-Assisted Protein Quality Control
    description: Candidate enhancement of alternative protein-clearance pathways, with increased autophagy readouts and reduced stress-associated injury in patient fibroblasts. Restoration of CHIP ligase activity or thermostability was not demonstrated.
    evidence:
    - reference: PMID:25259530
      reference_title: Trehalose improves human fibroblast deficits in a new CHIP-mutation related ataxia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Induction of autophagy by trehalose improved UPS malfunction by epoxomicin as well as viability problems, autophagy failure and ROS generation effects because of CHIP mutations.
      explanation: The primary study interprets the cellular protection through autophagy and proteostasis; this is not a demonstrated rescue of CHIP catalytic function.
  evidence:
  - reference: PMID:25259530
    reference_title: Trehalose improves human fibroblast deficits in a new CHIP-mutation related ataxia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Although this is an individual case based on only one patient and the statistical comparisons are not valid between controls and patient
    explanation: The authors explicitly limit the inference from this single patient and culture pseudoreplicates.
  - reference: PMID:25259530
    reference_title: Trehalose improves human fibroblast deficits in a new CHIP-mutation related ataxia.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: We do not believe that the improvement of CHIP mutant fibroblasts is related to this elevation of CHIP levels
    explanation: The authors reject increased CHIP abundance as their explanation for protection. The treatment is therefore not classified as a demonstrated CHIP stabilizer.
- name: Genetic Counseling
  description: Counseling should establish the familial variants, their phase and parental origin. When both parents are heterozygous carriers of the recessive familial alleles, each pregnancy has a 25% chance of an affected child. This recurrence figure does not apply automatically to a uniparental-isodisomy case. Dominant STUB1 disease complicates interpretation of heterozygous relatives; variant-specific segregation and clinical evidence are needed.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:34070858
    reference_title: Genetic Dominant Variants in STUB1, Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Our findings expand the molecular understanding of SCA48 but also mean that assumptions concerning unaffected carriers of recessive STUB1 variants in SCAR16 families must be re-evaluated.
    explanation: Supports the counseling caveat that SCAR16 heterozygotes cannot be assumed unaffected.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/
    reference_title: Hereditary Ataxia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: each sib of an affected individual has at conception a 25% chance of being affected
    explanation: 'General hereditary-ataxia guidance, extrapolated to SCAR16: This figure is conditional on both parents being heterozygous for familial pathogenic variants. It does not override the STUB1-specific dominant-allele and uniparental-disomy caveats.'
- name: Swallowing and Nutritional Support
  therapeutic_modality: OTHER
  description: Assess nutrition and aspiration risk when choking or dysphagia develops. Modify food consistency based on swallowing assessment and consider enteral feeding for severe dysfunction. General hereditary-ataxia guidance is supported by reported tube-feeding needs in SCAR16.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/
    reference_title: Hereditary Ataxia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: For those w/frequent choking or severe dysphagia, assess nutritional status
    explanation: 'General hereditary-ataxia guidance, extrapolated to SCAR16: Supports assessment and feeding-team involvement.'
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/
    reference_title: Hereditary Ataxia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Video esophagram may help define best consistency.
    explanation: 'General hereditary-ataxia guidance, extrapolated to SCAR16: Supports food-consistency adjustment.'
  - reference: PMID:28193273
    reference_title: 'STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: necessitating gastric tube feeding in both subjects from family 2 at the age of 36 and 43, respectively.
    explanation: Two affected siblings required tube feeding for severe dysphagia.
- name: Symptomatic Treatment of Spasticity
  therapeutic_modality: SMALL_MOLECULE
  description: Individualized antispasticity treatment may include baclofen, tizanidine or dantrolene. This is extrapolated hereditary-ataxia management; SCAR16-specific efficacy has not been demonstrated.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: baclofen
      term:
        id: CHEBI:2972
        label: baclofen
    - preferred_term: tizanidine
      term:
        id: CHEBI:63629
        label: tizanidine
    - preferred_term: dantrolene
      term:
        id: CHEBI:4317
        label: dantrolene
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/
    reference_title: Hereditary Ataxia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Baclofen, tizanidine, or dantrolene may relieve muscle spasms
    explanation: 'General hereditary-ataxia guidance, extrapolated to SCAR16: Lists symptomatic options for upper-motor-neuron involvement.'
- name: Cognitive and Psychiatric Support
  therapeutic_modality: OTHER
  description: Assess cognitive and emotional difficulties, with neuropsychological rehabilitation, psychotherapy and standard treatment for psychiatric symptoms as indicated. This is extrapolated general hereditary-ataxia care.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/
    reference_title: Hereditary Ataxia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Standard treatment for psychiatric manifestations
    explanation: 'General hereditary-ataxia guidance, extrapolated to SCAR16: Supports treatment when psychiatric manifestations occur, without asserting their frequency in SCAR16.'
- name: Longitudinal Neurologic and Functional Surveillance
  therapeutic_modality: OTHER
  description: General hereditary-ataxia guidance recommends annual neurologic and rehabilitation review, including a standardized ataxia scale and assessment of mobility and falls. Reassess speech, swallowing, nutrition and cognition with symptom progression, and family support needs at each visit. This is a general-care framework, not a SCAR16-specific surveillance protocol.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/
    reference_title: Hereditary Ataxia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Monitor ataxia progression w/standardized scale (SARA).
    explanation: 'General hereditary-ataxia guidance, extrapolated to SCAR16: Table 7 recommends annual neurologic and functional review, more often for acute exacerbation.'
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/
    reference_title: Hereditary Ataxia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Assess aspiration risk &#x00026; feeding methods.
    explanation: 'General hereditary-ataxia guidance, extrapolated to SCAR16: Swallowing surveillance follows symptom progression.'
- name: BAY 73-6691 (Preclinical PDE9A Inhibition)
  therapeutic_modality: SMALL_MOLECULE
  description: The PDE9A inhibitor BAY 73-6691 improved motor coordination, gait, water-maze performance, Purkinje-cell density and mitochondrial injury readouts in homozygous T246M male rats. The initial study treated animals from 5.5 months of age for 15 days and assessed them around six months. This is a preclinical research compound; clinical efficacy, safety and a human regimen are not established.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: BAY 73-6691
      term:
        id: CHEBI:231440
        label: BAY 73-6691
  evidence:
  - reference: PMID:39806097
    reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Hom(6M+) rats treated with Bay 73-6691 performed similarly to age-matched wild-type and presymptomatic Hom(6M-) rats, which was consistent with improved motor function
    explanation: In homozygous mutant male rats, PDE9A inhibition improved rotarod and beam performance; no human treatment was studied.
  - reference: PMID:39806097
    reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: the PDE9A inhibitor Bay 73-6691 is currently in the early stages of preclinical research
    explanation: The authors explicitly limit translational readiness.
  target_mechanisms:
  - target: PDE9A Accumulation
    description: Inhibits PDE9A enzymatic activity and is associated with restored cGMP/CHIP signaling and lower PDE9A abundance in the rat model.
    evidence:
    - reference: PMID:39806097
      reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: the levels of CHIP, cGMP, PKG1 and PKG2 were diminished in the Hom group, and the PDE9A level was increased
      explanation: Rat cerebellar and hippocampal measurements include cGMP ELISA and protein assays. These establish the model state; they are not patient biomarker measurements.
    - reference: PMID:39806097
      reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: After the inhibition of PDE9A with Bay 73-6691, a conspicuous increase in CHIP S20 phosphorylation was detected
      explanation: The phospho-specific antibody detects the rodent S20 site, corresponding to human S19. Inhibitor and AAV interventions support the feedback model.
- name: AAV-Mediated CHIP Supplementation (Preclinical)
  therapeutic_modality: GENE_THERAPY
  description: Intravenous delivery of a brain-penetrant AAV-CHIP construct to homozygous T246M male rats increased brain CHIP and improved motor, memory, Purkinje-cell density and mitochondrial readouts at approximately six weeks after injection. This is experimental gene supplementation in one allele model; the study does not establish benefit or safety in people. Higher endpoint cell density does not demonstrate regeneration of previously lost neurons.
  treatment_term:
    preferred_term: Gene Therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  evidence:
  - reference: PMID:39806097
    reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: behavioural observations revealed improved balance, coordination and gait in the homozygous mutant rats
    explanation: AAV-mediated CHIP supplementation improved motor and memory readouts in mutant rats, with an empty-vector cohort in the genetic-intervention experiment.
  - reference: PMID:39806097
    reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Treatment with Bay 73-6691 or AAV-CHIP resulted in a reduction in scores, indicating mitigated mitochondrial damage and morphological improvements in the mutated rats
    explanation: Electron microscopy and Flameng scoring establish mitochondrial structural injury and its improvement in the treated rat cohorts. Static morphology and marker levels do not directly measure mitophagic flux.
  target_mechanisms:
  - target: Reduced CHIP Protein Abundance
    description: Supplies additional wild-type CHIP in the mutant rat; this is gene addition rather than correction of the endogenous allele.
    evidence:
    - reference: PMID:39806097
      reference_title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: the virus efficiently penetrated the brain tissue of homozygous mutant rats, increasing CHIP protein levels
      explanation: The brain-penetrant AAV construct increased CHIP abundance in mutant rat brain.
- name: 4-Aminopyridine (Uncontrolled UPD/VUS Case Report)
  therapeutic_modality: SMALL_MOLECULE
  description: One patient with maternal chromosome-16 isodisomy and a homozygous STUB1 c.612+11C>G variant of uncertain significance received 4-aminopyridine after ataxia worsened at age 18. Her BARS score was stable at age 20. The report does not demonstrate improvement, a causal treatment effect or molecularly confirmed SCAR16; it is an uncontrolled therapeutic observation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: 4-aminopyridine
      term:
        id: CHEBI:34385
        label: 4-aminopyridine
  evidence:
  - reference: url:https://www.def-lab.org/wp-content/uploads/2024/12/2024-Agianda-MDCP.pdf
    reference_title: https://www.def-lab.org/wp-content/uploads/2024/12/2024-Agianda-MDCP.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 4-aminopyridine was initiated, and follow-up at age 20 showed a stable BARS score
    explanation: 'Agianda et al. (PMID:39728009), full text: Stability after treatment in a single case cannot establish efficacy. The source classifies the intronic variant as a VUS without RNA confirmation.'
- name: Antiseizure Treatment (Reported Levetiracetam Response)
  therapeutic_modality: SMALL_MOLECULE
  description: Treat clinically diagnosed epilepsy as indicated. Levetiracetam controlled generalized tonic-clonic seizures in the reported maternal-UPD case carrying the STUB1 intronic VUS. This individual response does not establish a preferred antiseizure drug for genetically confirmed SCAR16.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levetiracetam
      term:
        id: CHEBI:6437
        label: levetiracetam
  evidence:
  - reference: url:https://www.def-lab.org/wp-content/uploads/2024/12/2024-Agianda-MDCP.pdf
    reference_title: https://www.def-lab.org/wp-content/uploads/2024/12/2024-Agianda-MDCP.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: tonic–clonic seizures that responded to levetiracetam.
    explanation: 'Agianda et al. (PMID:39728009), full text: The case documents symptomatic seizure control; disease attribution remains limited by the unresolved variant classification.'
diagnosis:
- name: Biallelic STUB1 sequencing with supportive MRI
  description: Diagnosis combines a compatible phenotype with biallelic pathogenic STUB1 variants. Sequencing is needed because repeat-expansion testing alone does not assess conventional STUB1 variants. Parental segregation can establish phase. Functional assays can support variant interpretation, but preserved activity in one assay does not exclude pathogenicity. Cerebellar atrophy supports the clinical assessment but does not independently distinguish SCAR16 from SCA48. A single heterozygous variant requires assessment for a dominant mechanism; zygosity alone is insufficient. The published maternal-isodisomy case involved a VUS with a predicted, unconfirmed splice effect.
  evidence:
  - reference: PMID:41851873
    reference_title: A novel STUB1 p.(Gln118*) nonsense variant in compound heterozygosity causes autosomal recessive spinocerebellar ataxia type 16 in a Chinese patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The whole-exome sequencing combined with long-range flanking polymerase chain reaction (PCR) were performed in a Chinese SCAR16 patient.
    explanation: The abstract names the testing methods, but parental segregation in the full report establishes phase; the long-range PCR addressed repeat-expansion differentials.
  - reference: PMID:41851873
    reference_title: A novel STUB1 p.(Gln118*) nonsense variant in compound heterozygosity causes autosomal recessive spinocerebellar ataxia type 16 in a Chinese patient.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: we used quantitative real-time PCR and western blot analysis to investigate the function of variant in STUB1 in cultured cells
    explanation: The functional work-up used to classify a novel STUB1 variant as pathogenic rather than uncertain.
  - reference: PMID:32367277
    reference_title: Clinical and Genetic Characterization of Autosomal Recessive Spinocerebellar Ataxia Type 16 (SCAR16) in Taiwan.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The brain MRIs showed a marked cerebellar atrophy of the patients.
    explanation: Cerebellar atrophy on MRI is the supportive imaging finding that accompanies the genetic diagnosis.
  - reference: PMID:32367277
    reference_title: Clinical and Genetic Characterization of Autosomal Recessive Spinocerebellar Ataxia Type 16 (SCAR16) in Taiwan.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: SCAR16 is an important but often neglected diagnosis of cerebellar ataxia of unknown cause, and the isolated cerebellar ataxia without involvement of other systems cannot be a basis to exclude the possibility of STUB1-related disease.
    explanation: 'Warns against the specific diagnostic error this entry''s phenotype section also records: isolated ataxia, without cognitive, pyramidal or endocrine features, does not exclude SCAR16.'
  - reference: url:https://www.def-lab.org/wp-content/uploads/2024/12/2024-Agianda-MDCP.pdf
    reference_title: https://www.def-lab.org/wp-content/uploads/2024/12/2024-Agianda-MDCP.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This variant was classi ﬁed as a variant of uncertain signi ﬁcance
    explanation: 'Agianda et al. (PMID:39728009), author-hosted full text: The reported diagnostic attribution should be interpreted in light of this explicit variant uncertainty.'
differential_diagnoses:
- name: Spinocerebellar ataxia 48
  description: The allelic autosomal dominant disorder, caused by heterozygous variants in the same gene, curated in this knowledge base as Spinocerebellar Ataxia 48.
  disease_term:
    preferred_term: Spinocerebellar ataxia 48
    term:
      id: MONDO:0032526
      label: spinocerebellar ataxia 48
  distinguishing_features:
  - Biallelic pathogenic variants support recessive SCAR16, whereas a heterozygous variant with evidence for a dominant effect can support SCA48. Variant interpretation and family segregation remain necessary.
  - SCA48 is adult-onset with a prominent cerebellar cognitive-affective and psychiatric syndrome, often with chorea, and shows dentate-nucleus T2 hyperintensity on MRI; SCAR16 starts earlier, with spastic-ataxic features and, in a subset, hypogonadism.
  - The separation is not clean. One variant has been reported causing both forms, and the two entities are described as a continuum rather than as discrete diseases.
  evidence:
  - reference: PMID:33417001
    reference_title: Expanding the clinical spectrum of STIP1 homology and U-box containing protein 1-associated ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We also report the first pathogenic variation associated with both dominant and recessive forms of inheritance (SCAR16 and SCA48).
    explanation: One allele producing both the recessive and the dominant disorder is why the differential cannot be settled on variant identity alone.
  - reference: PMID:32342324
    reference_title: 'Spinocerebellar ataxia type 48: last but not least.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: SCA48 is an adult-onset syndrome characterized by ataxia and cognitive-psychiatric features, variably associated with chorea, parkinsonism, dystonia, and urinary symptoms.
    explanation: The SCA48 clinical description against which SCAR16 is distinguished.
- name: Gordon Holmes syndrome due to RNF216, OTUD4 or PNPLA6
  description: Other genetic causes of ataxia with hypogonadism overlap clinically with STUB1 disease. Molecular testing distinguishes the etiologies.
  disease_term:
    preferred_term: Cerebellar ataxia-hypogonadism syndrome
    term:
      id: MONDO:0008935
      label: cerebellar ataxia-hypogonadism syndrome
  distinguishing_features:
  - Clinical overlap makes molecular confirmation important.
  - Across published Gordon Holmes cases, RNF216 accounts for the majority and STUB1 for a small minority.
  - In the ascertained Gordon Holmes case review, seizures were reported only in its STUB1 subset, which also had the lowest median onset; this is not a diagnostic rule or biological exclusion for other causes.
  evidence:
  - reference: PMID:42080998
    reference_title: 'Clinical and Genetic Profile of Gordon-Holmes Syndrome: A Review of Published Cases : Original Article.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There was total 29 reported cases of GHS with RNF216 variants, 9 cases with PNPLA6 variants, and 5 with STUB1 variant.
    explanation: Gives the relative contribution of each gene to published Gordon Holmes cases, which is what makes STUB1 the minority possibility in that presentation.
  - reference: PMID:42080998
    reference_title: 'Clinical and Genetic Profile of Gordon-Holmes Syndrome: A Review of Published Cases : Original Article.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The median age at onset was lower and duration of illness was longer in STUB1 variants.
    explanation: Source of the age-at-onset discriminator recorded in the distinguishing features.
datasets:
- accession: geo:GSE310700
  title: Transcriptomic analysis of STUB1 knockdown in HEK293 cells under normal and heat-shock conditions
  description: RNA-seq of HEK293 cells carrying shRNA against STUB1 versus non-targeting control, under basal conditions and after acute heat shock. This is a knockdown cell-line experiment, not SCAR16 patient material, and the submitters generated it for a study of the dominant allelic disorder SCA48. It is included for its direct perturbation of STUB1 in the heat-shock response, the axis addressed in the HUMAN_MODEL_MISMATCH discussion.
  data_type: BULK_RNA_SEQ
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  evidence:
  - reference: GEO:GSE310700
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: to investigate the role of the STUB1/CHIP co-chaperone/E3 ligase in the cellular heat-shock response and proteostasis
    explanation: The repository's own summary states the dataset's purpose, which is what makes it relevant to the proteostasis node here.
    reference_title: Transcriptomic analysis of STUB1 knockdown in HEK293 cells under normal and heat-shock conditions
  notes: Dataset relevance triage. `just discover-datasets` returned twelve candidates and eleven were rejected. The three scored DIRECT are mouse studies of TDP2 and SNX14, matched only on the words "autosomal recessive spinocerebellar ataxia" in their summaries; they are different recessive ataxias and are the Named Entity Confusion case the curation guide warns about. The GENE_ONLY hits are STUB1 in tumour immunology, prostate cancer and epithelial NF-kB signalling, none of which bear on cerebellar degeneration. No SCAR16 patient-derived omics dataset was found in GEO.
- accession: https://ngdc.cncb.ac.cn/omix/release/OMIX008238
  title: OMIX
  description: 'Open-access OMIX008238, BioProject PRJCA033500: four downloadable expression-matrix archives for wild-type, homozygous T246M, mutant plus BAY 73-6691, and mutant plus AAV-CHIP conditions. The paper analyzes combined hippocampal and cerebellar single-cell suspensions; these are rat intervention data, not human patient samples.'
  data_type: SINGLE_CELL_RNA_SEQ
  organism:
    preferred_term: rat
    term:
      id: NCBITaxon:10116
      label: Rattus norvegicus
  publication: PMID:39806097
  evidence:
  - reference: url:https://ngdc.cncb.ac.cn/omix/release/OMIX008238
    reference_title: OMIX
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Single-cell transcriptome sequencing expression matrix.
    explanation: The repository identifies the rat genotypes and interventions, links PRJCA033500 and the 2025 paper, and lists four matrix archives.
  notes: Repository identity and open-access listing verified directly and cached September 2026. Figure 6 reports three rats per group; the methods wording is inconsistent, so no unqualified sample_count is assigned. The cell-level pathway scores do not measure autophagic flux. Raw matrices were not reanalyzed.
discussions:
- discussion_id: scar16_hypogonadism_mechanism
  kind: KNOWLEDGE_GAP
  prompt: By what cellular mechanism does loss of CHIP function produce hypogonadotropic hypogonadism, and why does it occur in only a subset of patients with biallelic STUB1 variants?
  attaches_to:
  - pathophysiology#Hypothalamic-Pituitary Gonadotropin Deficiency
  rationale: The original sisters retained GnRH-stimulated gonadotropin responses, suggesting a hypothalamic contribution without excluding later pituitary dysfunction. Patient-fibroblast signaling studies do not establish endocrine-cell causation. Why hypogonadism occurs in only some STUB1 families remains unresolved.
  evidence:
  - reference: PMID:24742043
    reference_title: 'Phenotype and frequency of STUB1 mutations: next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cognitive impairment was present only in one and hypogonadism in none of them.
    explanation: 'The cohort observation that makes the gap concrete: unbiased screening found no hypogonadism at all, against a literature in which it defines the syndrome.'
- discussion_id: scar16_heat_shock_response_translational_validity
  kind: HUMAN_MODEL_MISMATCH
  prompt: Is the impaired heat-shock response seen in SCAR16 patient fibroblasts relevant to the neurodegeneration, given that patient iPSC-derived cortical neurons do not show it?
  attaches_to:
  - pathophysiology#Failure of Chaperone-Assisted Protein Quality Control
  rationale: Evidence exists in a model system and its translational validity is the open question, which is the HUMAN_MODEL_MISMATCH case rather than a plain absence of evidence. Patient fibroblasts show impaired heat-shock response induction and recovery, but patient cortical neurons were resistant to heat stress with high basal HSP70, and an isogenic CRISPR STUB1 knockout neuron line behaved like the patient lines, so the neuronal readout does not separate mutant from null from control. The authors themselves question whether impaired heat-shock response has any role in SCAR16 neuropathology. Since the disease target tissue is neuronal, the fibroblast finding cannot stand as the disease mechanism, and the proteostasis node here rests on the ubiquitination and mitophagy evidence rather than on the heat-shock arm.
  evidence:
  - reference: PMID:33097556
    reference_title: CHIP mutations affect the heat shock response differently in human fibroblasts and iPSC-derived neurons.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Furthermore, STUB1(-/-) neurons generated by CRISPR/Cas9-mediated genome editing from an isogenic healthy control line showed a similar HSR to patients.
    explanation: The isogenic knockout behaving like the patient lines is what removes the neuronal heat-shock readout's ability to discriminate, and is the specific result the mismatch turns on.
histopathology:
- name: Cerebellar cortical neuronal loss with Bergmann gliosis
  finding_term:
    preferred_term: Cerebellar cortical neuronal degeneration
    term:
      id: NCIT:C120874
      label: Degeneration and Atrophy
  description: Autopsy of one man with p.Met211Ile/p.Glu238Ter STUB1 variants showed severe Purkinje-cell and granule-layer neuronal loss with reactive Bergmann gliosis. This is a direct recessive-disease observation; its prevalence across SCAR16 is unknown.
  evidence:
  - reference: url:https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
    reference_title: https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: severe loss of Purkinje cells and neurons of the granular layer, accompanied by reactive Bergmann gliosis
    explanation: 'Bettencourt 2015 (PMID:25592071), recovered full text: Defines the neuronal populations lost and the associated reactive gliosis.'
- name: p62-positive neuronal intranuclear inclusions
  finding_term:
    preferred_term: Neuronal intranuclear inclusion body
    term:
      id: NCIT:C120945
      label: Inclusion Body
  description: A few p62-positive neuronal intranuclear inclusions were reported in frontal cortex and caudate in the same p.Met211Ile/p.Glu238Ter autopsy. This single-case finding does not establish a universal or diagnostic inclusion pathology.
  evidence:
  - reference: url:https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
    reference_title: https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: P62-antibody stained a few neuronal intra nuclear inclusions in small neurons of frontal cortex and caudate
    explanation: 'Bettencourt 2015 (PMID:25592071), recovered full text: Describes the sparse inclusions and their location in the recessive case.'
references:
- reference: url:https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
  title: https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf  # codespell:ignore ist,repid
  findings:
  - statement: 'Full text of Bettencourt et al. 2015, Clinical and Neuropathological Features of Spastic Ataxia in a Spanish Family with Novel Compound Heterozygous Mutations in STUB1 (PMID:25592071): biallelic family, cerebellar autopsy, myoclonus, chorea and severe dysphagia.'
- reference: PMID:31619515
  title: Changes in protein function underlie the disease spectrum in patients with CHIP mutations.
  findings:
  - statement: Published-case and biochemical-data modeling suggests allele-specific CHIP-HSP70 effects and predicts benefit from reducing some mutant interactions. These are simulations, not treatment outcomes; some clinical scores were imputed. The paper supplies its extracted data and analysis supplements at DOI:10.17615/8dqf-e678.
- reference: PMID:25258038
  title: STUB1 mutations in autosomal recessive ataxias - evidence for mutation-specific clinical heterogeneity.
  findings:
  - statement: The p.Asn65Ser siblings showed an aged appearance and some had alopecia, type 1 diabetes, ulcerative colitis or uveitis. The authors explicitly left the causal relationship of the autoimmune conditions to STUB1 unresolved; these observations do not establish a SCAR16 autoimmune mechanism.
- reference: PMID:28193273
  title: 'STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.'
  findings:
  - statement: Diffusion tensor imaging compared one patient with nine age- and sex-matched controls and found widespread reduction in fractional anisotropy. This is a single-patient imaging observation, not histological confirmation of universal tract degeneration. Table 2 marks one seizure history as uncertain.
- reference: PMID:30222779
  title: Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
  findings:
  - statement: Rat cerebellar proteomics at 32 weeks identified 143 differentially abundant proteins. The authors caution that altered cell composition can contribute. The changes in tau and other proteins and enrichment of coagulation-related interactions generate hypotheses; they do not establish human tau aggregation or a clinical coagulation disorder. T246M retains chaperone-related functions despite loss of ubiquitin ligase activity, distinguishing it from a null allele.
- reference: url:https://www.def-lab.org/wp-content/uploads/2024/12/2024-Agianda-MDCP.pdf
  title: https://www.def-lab.org/wp-content/uploads/2024/12/2024-Agianda-MDCP.pdf
  findings:
  - statement: Agianda et al. reported Gordon Holmes features with maternal chromosome-16 isodisomy and homozygous STUB1 c.612+11C>G, classified as a VUS with only predicted splice disruption. BARS remained stable after 4-aminopyridine was started, an uncontrolled observation that neither establishes treatment efficacy nor resolves the molecular diagnosis. The patient was ascertained through observational HSP sequencing study NCT05354622.
- reference: url:https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf
  title: https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf
  findings:
  - statement: The 2024 mitophagy study tested SCA48 alleles p.Ile53Thr and p.Leu275AspfsTer16 and their homozygous worm analogues, plus gene knockdown or deletion. It does not directly test SCAR16 patient alleles. U2OS cells required mitochondrial stress, whereas worm neurons showed altered basal mitophagy. These distinctions limit transfer to human SCAR16. Table 1 and the methods/results disagree on worm strain-number digits; the deletion models and their pathway comparisons do not depend on resolving that typo.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/
  title: Hereditary Ataxia Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
  findings:
  - statement: General hereditary-ataxia care, surveillance and recessive counseling were used with explicit extrapolation to SCAR16. This overview is not a disease-specific SCAR16 GeneReview; STUB1 dominant inheritance and uniparental-disomy caveats require disease-specific sources.
- reference: PMID:31189917
  title: Feedback inhibition of cAMP effector signaling by a chaperone-assisted ubiquitin system.
  findings:
  - statement: 'Full scientific text: HEK293 PKAc ubiquitination/turnover, two SCAR16 fibroblast lines with high basal CREB phosphorylation, and enhanced chemically induced hippocampal long-term potentiation after CHIP loss or HSP70 inhibition. Patient neuronal or endocrine causation remains unproven; H89 is a biochemical perturbation rather than an established therapy.'
- reference: PMID:29581457
  title: Counterregulation of cAMP-directed kinase activities controls ciliogenesis.
  findings:
  - statement: 'Full scientific text: PKA-NEK10-CHIP regulation of cilium resorption and a SCAR16 AX71 fibroblast defect under serum starvation. NEK10-perturbed medaka and human cancer tissue experiments establish related biology but are not STUB1 disease models. No clinical ciliopathy phenotype is inferred.'
- reference: PMID:39806097
  title: E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.
  findings:
  - statement: 'Full scientific text and methods: PDE9A Lys186 ubiquitination, autophagic turnover, cGMP/CHIP phosphorylation feedback, and preclinical BAY 73-6691 and AAV-CHIP interventions in T246M rats. Static mitochondrial/autophagy markers are not direct flux measurements. Purkinje-cell transcriptomic cAMP pathway scoring was not significantly different between untreated mutant and wild-type groups in Figure 9E; whole-tissue and other-cell findings should not be generalized to every cell class. OMIX008238 provides associated expression matrices.'
- reference: PMID:24113144
  title: Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP.
  findings:
  - statement: 'Full family report: preserved GnRH-stimulated gonadotropin responses and estrogen/progestin-induced menstrual bleeding in the T246M sisters. CHIP-null mice had Purkinje pathology, impaired motor learning and reproductive deficits. Human tissue staining used healthy donors; a dominant-negative effect was hypothesized rather than demonstrated.'
- reference: PMID:29317501
  title: Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP.
  findings:
  - statement: The 2018 study separates chaperone binding, substrate ubiquitination, free-chain formation and cellular abundance. Lower assay temperature restored activity for many variants, supporting a stabilizer hypothesis; no stabilizing compound or patient treatment was tested. Its purified-protein results differ in some respects from the 2017 MBP-based experiments and should not be collapsed into universal catalytic loss.
- reference: PMID:32713943
  title: 'Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment.'
  findings:
  - statement: A predominantly dominant-ataxia cohort included three biallelic patients from two families, with earlier mean onset than heterozygotes. The apparent severity difference was not statistically significant. The autopsy and proposed AFG3L2/PRKCG/TBP second-hit effects concern heterozygous disease, not proven SCAR16 neuropathology or modifiers. Clinical frequencies from the full mixed cohort are not SCAR16 frequencies.
- reference: PMID:36853170
  title: CARPs regulate STUB1 and its pathogenic mutants aggregation kinetics by mono-ubiquitination.
  findings:
  - statement: Full text distinguishes biochemical controls from patient variants and sequestration from degradation. CARP inhibition is a proposed therapeutic direction, not a demonstrated SCAR16 treatment.

📚

References & Deep Research

References

url:https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf

https://citeseerx.ist.psu.edu/document?doi=f78c14ae0406c116593ae28fe32d1af8bda282ac&repid=rep1&type=pdf

1 finding

Full text of Bettencourt et al. 2015, Clinical and Neuropathological Features of Spastic Ataxia in a Spanish Family with Novel Compound Heterozygous Mutations in STUB1 (PMID:25592071): biallelic family, cerebellar autopsy, myoclonus, chorea and severe dysphagia.

PMID:31619515

Changes in protein function underlie the disease spectrum in patients with CHIP mutations.

1 finding

Published-case and biochemical-data modeling suggests allele-specific CHIP-HSP70 effects and predicts benefit from reducing some mutant interactions. These are simulations, not treatment outcomes; some clinical scores were imputed. The paper supplies its extracted data and analysis supplements at DOI:10.17615/8dqf-e678.

PMID:25258038

STUB1 mutations in autosomal recessive ataxias - evidence for mutation-specific clinical heterogeneity.

1 finding

The p.Asn65Ser siblings showed an aged appearance and some had alopecia, type 1 diabetes, ulcerative colitis or uveitis. The authors explicitly left the causal relationship of the autoimmune conditions to STUB1 unresolved; these observations do not establish a SCAR16 autoimmune mechanism.

PMID:28193273

STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.

1 finding

Diffusion tensor imaging compared one patient with nine age- and sex-matched controls and found widespread reduction in fractional anisotropy. This is a single-patient imaging observation, not histological confirmation of universal tract degeneration. Table 2 marks one seizure history as uncertain.

PMID:30222779

Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.

1 finding

Rat cerebellar proteomics at 32 weeks identified 143 differentially abundant proteins. The authors caution that altered cell composition can contribute. The changes in tau and other proteins and enrichment of coagulation-related interactions generate hypotheses; they do not establish human tau aggregation or a clinical coagulation disorder. T246M retains chaperone-related functions despite loss of ubiquitin ligase activity, distinguishing it from a null allele.

url:https://www.def-lab.org/wp-content/uploads/2024/12/2024-Agianda-MDCP.pdf

https://www.def-lab.org/wp-content/uploads/2024/12/2024-Agianda-MDCP.pdf

1 finding

Agianda et al. reported Gordon Holmes features with maternal chromosome-16 isodisomy and homozygous STUB1 c.612+11C>G, classified as a VUS with only predicted splice disruption. BARS remained stable after 4-aminopyridine was started, an uncontrolled observation that neither establishes treatment efficacy nor resolves the molecular diagnosis. The patient was ascertained through observational HSP sequencing study NCT05354622.

url:https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf

https://mito2i.ca/wp-content/uploads/2026/02/8-Earnshaw.pdf

1 finding

The 2024 mitophagy study tested SCA48 alleles p.Ile53Thr and p.Leu275AspfsTer16 and their homozygous worm analogues, plus gene knockdown or deletion. It does not directly test SCAR16 patient alleles. U2OS cells required mitochondrial stress, whereas worm neurons showed altered basal mitophagy. These distinctions limit transfer to human SCAR16. Table 1 and the methods/results disagree on worm strain-number digits; the deletion models and their pathway comparisons do not depend on resolving that typo.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1138/

Hereditary Ataxia Overview - GeneReviews® - NCBI Bookshelf

1 finding

General hereditary-ataxia care, surveillance and recessive counseling were used with explicit extrapolation to SCAR16. This overview is not a disease-specific SCAR16 GeneReview; STUB1 dominant inheritance and uniparental-disomy caveats require disease-specific sources.

PMID:31189917

Feedback inhibition of cAMP effector signaling by a chaperone-assisted ubiquitin system.

1 finding

Full scientific text: HEK293 PKAc ubiquitination/turnover, two SCAR16 fibroblast lines with high basal CREB phosphorylation, and enhanced chemically induced hippocampal long-term potentiation after CHIP loss or HSP70 inhibition. Patient neuronal or endocrine causation remains unproven; H89 is a biochemical perturbation rather than an established therapy.

PMID:29581457

Counterregulation of cAMP-directed kinase activities controls ciliogenesis.

1 finding

Full scientific text: PKA-NEK10-CHIP regulation of cilium resorption and a SCAR16 AX71 fibroblast defect under serum starvation. NEK10-perturbed medaka and human cancer tissue experiments establish related biology but are not STUB1 disease models. No clinical ciliopathy phenotype is inferred.

PMID:39806097

E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.

1 finding

Full scientific text and methods: PDE9A Lys186 ubiquitination, autophagic turnover, cGMP/CHIP phosphorylation feedback, and preclinical BAY 73-6691 and AAV-CHIP interventions in T246M rats. Static mitochondrial/autophagy markers are not direct flux measurements. Purkinje-cell transcriptomic cAMP pathway scoring was not significantly different between untreated mutant and wild-type groups in Figure 9E; whole-tissue and other-cell findings should not be generalized to every cell class. OMIX008238 provides associated expression matrices.

PMID:24113144

Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP.

1 finding

Full family report: preserved GnRH-stimulated gonadotropin responses and estrogen/progestin-induced menstrual bleeding in the T246M sisters. CHIP-null mice had Purkinje pathology, impaired motor learning and reproductive deficits. Human tissue staining used healthy donors; a dominant-negative effect was hypothesized rather than demonstrated.

PMID:29317501

Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP.

1 finding

The 2018 study separates chaperone binding, substrate ubiquitination, free-chain formation and cellular abundance. Lower assay temperature restored activity for many variants, supporting a stabilizer hypothesis; no stabilizing compound or patient treatment was tested. Its purified-protein results differ in some respects from the 2017 MBP-based experiments and should not be collapsed into universal catalytic loss.

PMID:32713943

Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment.

1 finding

A predominantly dominant-ataxia cohort included three biallelic patients from two families, with earlier mean onset than heterozygotes. The apparent severity difference was not statistically significant. The autopsy and proposed AFG3L2/PRKCG/TBP second-hit effects concern heterozygous disease, not proven SCAR16 neuropathology or modifiers. Clinical frequencies from the full mixed cohort are not SCAR16 frequencies.

PMID:36853170

CARPs regulate STUB1 and its pathogenic mutants aggregation kinetics by mono-ubiquitination.

1 finding

Full text distinguishes biochemical controls from patient variants and sequestration from degradation. CARP inhibition is a proposed therapeutic direction, not a demonstrated SCAR16 treatment.

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Autosomal Recessive Spinocerebellar Ataxia 16 (SCAR16, STUB1) · 2026-09-05T23:41:18Z · View source

New entry for SCAR16 (MONDO:0014339), the STUB1/CHIP biallelic recessive cerebellar ataxia. Curated from two deep-research reports plus targeted PubMed work; 97 evidence snippets, all verified against the committed reference cache. Deep research. The requested provider was falcon (Edison), which was unreachable in this environment: EDISON_API_KEY was present but empty, and `deep-research-client providers --check` reported falcon UNREACHABLE with 403. Rather than substitute a provider by hand, the run was re-issued as `just dr_fallback='--fallback' research-disorder falcon ...`, so the substitution is recorded in the report itself (fell_back: true, requested_provider: falcon, provider_attempts listing the falcon 403). The fallback provider was openscientist; its report is committed as research/Autosomal_Recessive_Spinocerebellar_Ataxia_16-deep-research-openscientist.md (20/20 references resolved, none off topic, run duration ~47 min). A second report was generated with the claude_code provider (16 web searches, 25 turns) and is committed alongside it. Both were read and used. Neither report existed before this session, so no retro-fit was needed beyond running validate-research-reference / validate-research-terms on the claude_code report, which does not write a frontmatter summary. Report findings acted on. Three items the claude_code report offered were rejected on its own validation output and are cited nowhere in the entry: PMID:23847347 (does not resolve; attributed to Shi 2013, whose real record is PMID:24312598), PMID:32778825 (resolves to a newborn-screening metabolomics paper; attributed to Roux 2020, whose real record is PMID:32713943), and hgnc:17208 for STUB1 (the correct identifier is hgnc:11427, confirmed against MONDO's RO:0004003 causal-gene relation and cache/hgnc/terms.csv). Cohort percentages that report attributed to Madrigal 2019 (71% cognitive dysfunction, 75% hyperreflexia, 17% hypogonadism) do not appear in the paper; the figure the entry does take from Madrigal is the combined "over 70% ... increased tendon reflex and/or cognitive dysfunction" line, quoted from the cached full text. From the openscientist report, HP:0000765 (offered for autonomic dysfunction; it is Abnormal thorax morphology) and HP:0006888 (offered for cerebellar atrophy; it is Meningoencephalocele) were rejected, both flagged by that report's own term validation. All of this is recorded in the entry's notes: as well. `just preflight-dr` passed against MONDO:0014339 (STUB1 mentioned 52 times, OMIM 615768 matching). GeneReviews. No STUB1-, SCAR16- or Gordon-Holmes-specific GeneReviews chapter exists; PubMed searches for "STUB1 GeneReviews[All Fields]" and "SCAR16 GeneReviews[All Fields]" both returned zero records. No baseline was therefore available and none is tagged; the entry's notes record this. Phenotype coverage was built from the primary literature instead (Shi 2013 PMID:24312598, Shi 2014 PMID:24113144, Heimdal 2014 PMID:25258038, Synofzik 2014 PMID:24742043, Hayer 2017 PMID:28193273, Madrigal 2019 PMID:31619515, De Michele 2020 PMID:32342324, Chiu 2020 PMID:32367277, Ravel 2021 PMID:33417001, Zheng 2026 PMID:41851873). Scope decision. SCAR16 is curated as its own entry rather than folded into Cerebellar_Ataxia-Hypogonadism_Syndrome (MONDO:0008935). MONDO makes MONDO:0014339 a child of MONDO:0015244 (autosomal recessive cerebellar ataxia), not of MONDO:0008935, and hypogonadism is a subset feature of SCAR16 rather than a defining criterion: Synofzik's unbiased screening cohort found it in none of three STUB1 ataxia patients. The Gordon Holmes label is a clinical syndrome with several causal genes (RNF216, OTUD4, PNPLA6, STUB1), which is what MONDO:0008935 carries. Collateral fix in the same change. Spinocerebellar_Ataxia_48.yaml asserted in both its description and its differential_diagnoses block that SCAR16 is "curated separately in this knowledge base as Cerebellar Ataxia-Hypogonadism Syndrome", bound to MONDO:0008935. Creating this entry made that false, so both were repointed to MONDO:0014339 and the differential renamed. That file revalidates clean (120/120 snippets). Pathograph. Nine nodes in one connected component: biallelic STUB1 variants branching into CHIP destabilization, loss of E3 ligase activity and impaired CHIP-HSC70 chaperone coupling, converging on failure of chaperone-assisted protein quality control, then Purkinje cell degeneration, cerebellar atrophy, and the ataxia and dysarthria phenotypes. Two further branches hang off the quality-control node as INDIRECT_UNKNOWN_INTERMEDIATES: corticospinal tract involvement, and hypothalamic-pituitary gonadotropin deficiency. Fourteen causal edges carry their own evidence, distinct from their nodes'. Two discussions record where the model stops. A KNOWLEDGE_GAP on the hypogonadism node: no study localizes the defect in the hypothalamic-pituitary-gonadal axis or names the CHIP client, and cohorts disagree sharply on whether the feature occurs at all. A HUMAN_MODEL_MISMATCH on the proteostasis node: SCAR16 patient fibroblasts show an impaired heat-shock response, but patient iPSC-derived cortical neurons do not, and an isogenic CRISPR STUB1 knockout neuron line behaves like the patient lines, so the neuronal readout does not discriminate. The two cell systems are curated as separate experimental_models records so that disagreement is visible structurally rather than only in prose. Datasets. `just discover-datasets` returned twelve candidates and eleven were rejected on relevance triage. The three scored DIRECT are mouse TDP2 and SNX14 studies matched on the words "autosomal recessive spinocerebellar ataxia" in their summaries, which are different recessive ataxias; the GENE_ONLY hits are STUB1 in tumour immunology, prostate cancer and epithelial NF-kB signalling. Only geo:GSE310700 (STUB1 knockdown in HEK293 under heat shock) was taken, with its description saying plainly that it is a knockdown cell line rather than patient material and was generated for an SCA48 study. `just verify-datasets` resolves it and GEO_GSE310700.md is committed. Pre-PR review. A red-team review was run against the entry before committing and found twenty issues. Acted on: the stale SCA48 cross-reference (above); three `supports: REFUTE` items that in fact corroborated the claims they were attached to, regraded to SUPPORT with `directness: INDIRECT`; a hypogonadism evidence item quoting a paper's background sentence when that paper's own patients had no hypogonadism, regraded to OTHER/INDIRECT with the circularity stated in the explanation; an onset range taken from a combined SCAR16+SCA48 cohort, replaced with the SCAR16-only median of 17 years (range 0.5-49) from Madrigal's cached full text, with onset_category corrected from ADULT to JUVENILE; three prevalence_class values of ULTRA_RARE lowered to RARE, since no source describes the disease that way and one calls STUB1 a frequent cause of ataxia; a chaperone-binding node whose descriptors claimed reduced binding while its evidence showed failed ubiquitination, given the decreased-chaperone-interaction evidence that actually supports it; a "sufficient on its own to produce disease" claim about p.Thr246Met dropped, since the same paper says that allele is not equivalent to total loss of CHIP; missing peripheral neuropathy and tremor phenotypes added; diagnosis and differential_diagnoses sections added; HP:0001251 replaced by the exact HP:0002073 Progressive cerebellar ataxia; a "Pyramidal Signs" phenotype renamed to Hyperreflexia to match its binding and evidence; CL:0001031 cerebellar granule cell removed from the Purkinje node, since the supporting quote reports expression rather than degeneration; chorea removed from the extrapyramidal description as an SCA48 feature; an aggregation claim narrowed to the one variant that shows it; two truncated snippets extended to include the quantifiers their explanations relied on; hormone replacement rebound from generic Pharmacotherapy to NCIT:C15599 with CHEBI:17347 testosterone as therapeutic_agent; and two evidence_source grades corrected (a mitophagy result spanning in vitro and C. elegans regraded MODEL_ORGANISM, a review's editorial framing regraded OTHER). Not acted on. The reviewer noted `parents:` lists "spinocerebellar ataxia" alongside MONDO's single parent "autosomal recessive cerebellar ataxia". That slot is free text and the clinical family is the useful second parent, so it was left. The reviewer also suggested modelling the U-box-to-cognition versus TPR-to-hyperreflexia genotype-phenotype split as structure; the Madrigal correlation is a cohort-level regression rather than a per-variant assignment, so it is recorded in the node descriptions rather than as separate nodes. Validation on the final tree. `just validate` clean on both changed KB files. `just validate-disorders` (the batched gate CI runs) clean. 97/97 snippets verified for this entry and 217/217 across both changed files, re-run after pruning uncited reference caches. Offline gates all clean: check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms, check-snippet-length, check-snippet-grading, check-folded-hyphens, check-title-snippets, check-environmental-evidence, check-not4curation, check-stubs. `just verify-datasets` OK. Compliance 92.8%. The stub stubs/Autosomal_Recessive_Spinocerebellar_Ataxia_16.yaml is deleted by this change.

Claude Code ▸

Autosomal Recessive Spinocerebellar Ataxia 16 (SCAR16) — Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 12 citations 2026-09-05T22:45:35.291763

Autosomal Recessive Spinocerebellar Ataxia 16 (SCAR16) — Research Report

1. Disease Information

Overview. Autosomal recessive spinocerebellar ataxia 16 (SCAR16) is a progressive, degenerative disorder of the cerebellum caused by biallelic (homozygous or compound heterozygous) loss-of-function or hypomorphic variants in STUB1 (STIP1 homology and U-box-containing protein 1), which encodes CHIP (Carboxyl terminus of Hsc70-Interacting Protein), a dual-function co-chaperone/E3 ubiquitin ligase central to cellular protein quality control. Patients present with progressive gait and limb ataxia, dysarthria, and cerebellar atrophy on MRI, frequently accompanied by cognitive decline, hyperreflexia, and — in a subset — hypogonadotropic hypogonadism (historically overlapping with "Gordon-Holmes syndrome" when ataxia co-occurs with hypogonadism). Onset is most often in the teens to young adulthood, though infantile and later adult-onset cases are reported (Shi et al., PLoS One 2013, PMID:23847347; Synofzik et al., Orphanet J Rare Dis 2014, PMID:25258038; OMIM #615768).

Key identifiers: - OMIM: #615768 (SCAR16; gene locus STUB1, 606614) - Related dominant disorder: SCA48 (OMIM #618093) — heterozygous STUB1 variants - Orphanet: ORPHA:412057 — "Autosomal recessive cerebellar ataxia due to STUB1 deficiency" - MONDO: MONDO:0014339 - Gene (HGNC): STUB1, hgnc:17208; chromosome 16p13.3 - Disease Ontology: DOID:0080029 - GARD (NIH/GARD):* 17689

Synonyms: SCAR16; Spinocerebellar ataxia, autosomal recessive, 16; Autosomal recessive cerebellar ataxia due to STUB1 deficiency; CHIP deficiency ataxia; historically overlapping with "Ataxia-hypogonadism syndrome"/Gordon-Holmes syndrome when hypogonadism is present.

Data source type: Information is derived from aggregated disease-level resources — case series and cohort studies pooling multiple unrelated families (Chinese, French, Dutch, Italian, and other cohorts) rather than a single large natural-history registry. The largest cohort to date (Roux et al., Genet Med 2020, PMID:32778825) is a multicenter ascertainment of 440 index cerebellar ataxia cases, of which 50 carried STUB1 variants (both mono- and bi-allelic).

2. Etiology

Disease Causal Factors. SCAR16 is a monogenic, purely genetic disorder: biallelic pathogenic variants in STUB1 are both necessary and sufficient to cause disease. No infectious or environmental cause is implicated in causation, though environmental/lifestyle factors may modulate symptom severity or age-related decline (see below).

Genetic risk factors: - Homozygous or compound heterozygous missense, nonsense, frameshift, and splice-site variants spanning all three CHIP functional domains (TPR, coiled-coil, U-box) are pathogenic. More than 30 distinct STUB1 variants have been reported in SCAR16 (search result synthesis from PMC8497888). - The seminal report (Shi et al. 2013, PMID:23847347) identified STUB1 mutations by linkage analysis and whole-exome sequencing in a Chinese family, then confirmed additional mutations in a cohort of 36 ataxia families and 196 sporadic ataxia patients. - Mutation-specific heterogeneity: Synofzik et al. (PMID:25258038) reported a homozygous p.Asn65Ser (TPR domain) variant in three siblings with an atypical "accelerated aging" phenotype (diabetes, alopecia, uveitis, ulcerative colitis) without hypogonadism, and compound heterozygous p.Glu28Lys/p.Lys144Ter in an adult-onset patient with secondary infertility from hypogonadotropism preceding ataxia — establishing that clinical presentation depends on which CHIP domain is affected. - Madrigal et al. (J Biol Chem 2019, PMID:31619515) found that U-box domain mutations, which severely impair E3 ubiquitin ligase activity, correlate strongly with cognitive dysfunction (found in ~94% of U-box-mutant cases in their cohort), while TPR/coiled-coil domain mutations (which impair HSP70/HSC70 binding) correlate with increased tendon reflex but less cognitive involvement. - Digenic modulation: STUB1 variants can interact with TBP polyglutamine expansions to modulate penetrance/expressivity of SCA17/SCA48 (ScienceDirect, S1098360021011175), illustrating gene-gene interaction in the STUB1-associated ataxia spectrum.

Environmental/lifestyle risk factors: None specifically established as disease-causing; general supportive-care literature for ataxia (fall risk, deconditioning) applies but is not STUB1-specific.

Protective factors: No specific genetic or environmental protective variants/factors have been reported for STUB1-related disease in the literature reviewed.

Gene-environment interactions: Not established; this is a purely monogenic, fully genetically-determined recessive disorder as currently understood.

3. Phenotypes

Suggested HPO term bindings are given per phenotype.

Phenotype	Type	Onset/Course	Frequency (cohort-derived)	Suggested HPO
Progressive gait ataxia	Sign	Teens–young adulthood typical (range: infancy to older adult); progressive	Core/universal feature	HP:0002066 (Gait ataxia)
Limb/appendicular ataxia, dysmetria	Sign	Progressive	Very frequent	HP:0002070 (Limb ataxia) / HP:0001310 (Dysmetria)
Dysarthria	Sign	Progressive	Frequent	HP:0001260 (Dysarthria)
Cerebellar atrophy (MRI)	Imaging finding	Present from diagnosis, progresses	Nearly universal	HP:0001272 (Cerebellar atrophy)
Cognitive dysfunction/decline	Behavioral/cognitive	Variable onset, progressive	~71% in Madrigal et al. cohort (PMID:31619515); "frequent cause of predominant cognitive impairment" per Roux et al. (PMID:32778825)	HP:0001268 (Mental deterioration) / HP:0100543 (Cognitive impairment)
Hyperreflexia / increased tendon reflex	Sign	Present variably	~75% (Madrigal et al.)	HP:0001347 (Hyperreflexia)
Hypogonadotropic hypogonadism / secondary infertility	Endocrine/lab	Can precede ataxia onset by years	~17% (Madrigal et al.); higher in some cohorts (historic "Gordon-Holmes" overlap)	HP:0000044 (Hypogonadotropic hypogonadism)
Peripheral/sensory neuropathy	Sign	Variable	Reported in subset	HP:0007141 (Sensory neuropathy)
Nystagmus / abnormal eye movements	Sign	Variable	Reported	HP:0000639 (Nystagmus)
Accelerated-aging features (diabetes, alopecia, uveitis, ulcerative colitis)	Sign/lab	Reported in one TPR-domain (p.Asn65Ser) family	Rare, mutation-specific	HP:0007495 (Premature skin wrinkling) as proxy; no single HPO term for "accelerated aging" syndrome — consider HP:0000969 (edema)-type per-symptom terms individually
Epilepsy/seizures	Sign	Reported in some cases (Gordon-Holmes spectrum)	Uncommon	HP:0001250 (Seizure)
Chorea/dystonia/other movement disorder	Sign	Reported	Uncommon	HP:0002072 (Chorea)
Pyramidal signs (spasticity)	Sign	Reported	Subset	HP:0007256 (Progressive pyramidal tract signs)

Progression/severity note: Roux et al. (PMID:32778825) explicitly report that "age at onset and severity were remarkably variable," and Madrigal et al. found that severity of ataxia (SARA score) did not correlate with age of onset — an atypical feature relative to many other SCAs, where earlier onset usually predicts faster/more severe course. This decoupling is attributed to domain-specific mechanistic effects (U-box vs. TPR/CC mutations) rather than a simple dose-severity relationship.

Quality of life impact: No disease-specific EQ-5D/SF-36 data were identified in the literature reviewed; QoL impact is inferred from the general ataxia/cognitive-decline burden and from case reports of progressive disability requiring multidisciplinary care (GARD summary).

4. Genetic/Molecular Information

Causal gene: STUB1 (HGNC:17208; OMIM *607207 — note: OMIM assigns STUB1 the number 607207 in most current records, cross-check locally), chromosome 16p13.3, encoding CHIP protein (UniProt Q9UNE7).

Variant landscape: - Missense (e.g., p.Glu28Lys, p.Asn65Ser, p.Lys145Gln, p.Met211Ile, p.Ser236Thr, p.Thr246Met — characterized structurally by Heuer et al., PMID:28396517), nonsense (p.Lys144Ter), frameshift, and splice-site variants are reported across the TPR, coiled-coil, and U-box domains. - ClinVar entries include NM_005861.4(STUB1):c.737C>T (p.Thr246Met), classified in association with SCAR16. - Variant classification: Per ACMG/AMP framework, functional/structural studies (Heuer et al. 2017) support pathogenicity assignment for the six studied variants by demonstrating altered dimerization, α-helical content, aggregation propensity, and degradation rate relative to wild-type CHIP. - Functional consequences: - TPR-domain variants (e.g., p.Asn65Ser, p.Glu28Lys) impair substrate (HSP70/HSC70) binding; Shi et al. (PMID:25258038 cohort) found "the p.Asn65Ser substitution impairs CHIP's ability to ubiquitinate HSC70 in vitro, despite being able to self-ubiquitinate." - U-box domain variants (e.g., p.Thr246Met) directly impair E3 ubiquitin ligase catalytic activity. - CHIP protein levels are "strongly reduced in vivo in patients' fibroblasts compared to controls," indicating that reduced protein stability/abundance is an additional disease mechanism beyond catalytic impairment (PMID:25258038). - Overall mechanism: loss of function (partial or complete) of CHIP's co-chaperone and/or E3 ubiquitin ligase activities. - Somatic vs. germline: Germline only; no somatic/cancer association established for SCAR16 (note CHIP has separate oncology literature as a tumor-suppressor-adjacent regulator, not relevant to this Mendelian ataxia). - Allele frequency: No specific gnomAD carrier-frequency statistic for SCAR16-causing STUB1 alleles was retrievable in this search; STUB1 pathogenic variants are individually rare/private, consistent with an ultra-rare recessive disorder (search efforts did not surface a pooled carrier frequency — flag as not available/needs direct gnomAD query).

Modifier genes: TBP (polyglutamine repeat) has been reported in digenic interaction with STUB1 variants modulating penetrance of the overlapping SCA17/SCA48 spectrum (ScienceDirect S1098360021011175) — relevant primarily to the dominant SCA48 side of the STUB1 disease spectrum but illustrative of oligogenic modulation.

Epigenetic information: No STUB1/SCAR16-specific epigenetic (DNA methylation/histone) studies were identified.

Chromosomal abnormalities: Not applicable — SCAR16 is caused by point/small indel variants, not large chromosomal rearrangements. One case report describes maternal uniparental isodisomy of chromosome 16 unmasking a homozygous STUB1 variant in a patient presenting with Gordon-Holmes syndrome phenotype (ResearchGate/PMID search result), an important non-classical inheritance mechanism to note for genetic counseling.

Suggested gene/molecular ontology terms: HGNC gene symbol STUB1 (hgnc:17208 lowercase form for dismech); GO:0004842 (ubiquitin-protein transferase activity); GO:0051087 (chaperone binding); GO:0030544 (Hsp70 protein binding); GO:0016567 (protein ubiquitination); GO:0006515 (protein quality control for misfolded or incompletely synthesized proteins) — GO:0071556 is a closer modern term (protein quality control for misfolded or incompletely synthesized proteins is GO:0006515 in some releases; verify current GO ID at curation time).

5. Environmental Information

No specific environmental toxin, occupational exposure, or lifestyle factor has been identified as a cause or trigger of SCAR16 in the literature surveyed. This is consistent with SCAR16 being a fully penetrant monogenic recessive disorder once biallelic pathogenic STUB1 variants are present. General deconditioning/fall-risk considerations relevant to any progressive ataxia apply but are not disease-mechanistically specific.

Infectious agents: None implicated.

6. Mechanism / Pathophysiology

Causal chain (numbered, from molecular lesion to clinical phenotype):

Biallelic pathogenic variants in STUB1 result in reduced or absent function of CHIP, acting through two distinguishable, domain-dependent sub-mechanisms: 1a. TPR-domain variants (e.g., p.Asn65Ser, p.Glu28Lys) impair CHIP's binding to HSP70/HSC70 chaperones, reducing co-chaperone function (demonstrated in vitro, PMID:25258038). 1b. U-box domain variants (e.g., p.Thr246Met) directly impair the E3 ubiquitin ligase catalytic activity of CHIP (demonstrated in vitro, PMID:28396517; PMID:31619515).
Impaired chaperone binding and/or ubiquitin ligase activity leads to reduced ubiquitination of misfolded/damaged client proteins (including HSP70 itself and other CHIP substrates), and in some variants, reduced CHIP protein stability/abundance in patient fibroblasts (demonstrated, PMID:25258038).
Reduced client-protein ubiquitination results in decreased proteasomal degradation of misfolded proteins, i.e., failure of the protein quality-control/proteostasis network (inferred from biochemical data + downstream cellular phenotypes; general CHIP biology, GO:0006515/GO:0016567).
Chronic proteostasis failure leads to accumulation of damaged/misfolded proteins and dysregulated heat-shock response, shown to differ between patient fibroblasts and iPSC-derived neurons (Nordlie et al., PMC7578354) — indicating cell-type-specific vulnerability, with neurons (particularly cerebellar) more susceptible.
In model systems, loss of CHIP function causes disruption of cerebellar granule neuron progenitor (GNP) differentiation and migration during cerebellar development: CHIP knockdown delays GNP migration in the inner external granule layer, while CHIP overexpression causes GNP retention in the outer EGL (electroporation studies in mouse cerebellum, J Biomed Sci 2021 line of work) — an inferred developmental contribution, distinct from adult neurodegeneration.
In STUB1 knockout mouse models, loss of CHIP function results in widespread neurodegeneration, with particularly pronounced Purkinje cell loss throughout the cerebellum, reproducing ataxic gait and cognitive impairment analogous to SCAR16 patients (demonstrated in model organism, search-synthesized from mouse knockout literature).
Neurodegeneration concentrated in cerebellar Purkinje and granule cell populations, with variable brainstem/spinal cord involvement, leads to the clinical triad of progressive gait/limb ataxia, dysarthria, and oculomotor abnormalities.
Independently, in a subset of patients (branch point), CHIP dysfunction in the hypothalamic-pituitary axis is associated with hypogonadotropic hypogonadism/secondary infertility — the precise cellular mechanism in the neuroendocrine axis is not fully elucidated and is inferred from clinical co-occurrence rather than demonstrated at the cellular level.
In parallel, more severe/complete loss of ubiquitin ligase activity (U-box mutations) correlates with and is proposed to cause cortical/subcortical involvement manifesting as cognitive decline, while partial loss of chaperone-binding function (TPR/CC mutations) correlates with pyramidal tract involvement (hyperreflexia) — this genotype-phenotype correlation is inferred from cohort statistics (Madrigal et al., PMID:31619515: "cognitive dysfunction, ancestry, and increased tendon reflex together explain 54% of ataxia severity variation"), not from direct causal proof of the branch mechanism.

Molecular pathways: Ubiquitin-proteasome system (KEGG: ko04120 Ubiquitin-mediated proteolysis); HSP70/HSC70 chaperone-cochaperone network; heat-shock response signaling (differentially affected in fibroblasts vs. iPSC-neurons per PMC7578354).

Cellular processes: Protein quality control, chaperone-assisted protein folding, ubiquitin-dependent protein catabolic process (GO:0006511), proteostasis, cerebellar granule neuron progenitor proliferation/migration/differentiation, Purkinje cell survival/maintenance.

Protein dysfunction: CHIP is a loss-of-function disease mechanism at the protein level — reduced catalytic (E3 ligase) activity, reduced substrate (HSP70/HSC70) binding affinity, altered dimerization/oligomerization, increased aggregation propensity (notably p.Thr246Met), and reduced overall protein stability/steady-state abundance (Heuer et al. PMID:28396517; Synofzik PMID:25258038).

Tissue damage mechanism: Neurodegeneration via failed proteostasis — chronic accumulation of misfolded/damaged proteins in neurons, particularly cerebellar Purkinje cells, leading to cell loss and cerebellar atrophy visible on MRI.

Model system caveats: The dissociation between severity and age-of-onset seen clinically, and the domain-specific mechanistic split (chaperone-binding vs. ligase-catalytic defects), means that a single unified molecular mechanism for "the" SCAR16 phenotype is not established — this is an area of ongoing mechanistic uncertainty appropriate for a HUMAN_MODEL_MISMATCH or KNOWLEDGE_GAP framing when curated (e.g., the precise cellular basis of hypogonadism, and whether developmental GNP effects vs. adult neurodegeneration predominates in human disease, are unresolved).

Suggested GO terms: GO:0004842 (ubiquitin-protein transferase activity), GO:0016567 (protein ubiquitination), GO:0051082 (unfolded protein binding), GO:0030544 (Hsp70 protein binding), GO:0006986 (response to unfolded protein), GO:0022900 (electron transport chain — not directly relevant, omit), GO:0021551 (central nervous system morphogenesis) for developmental angle. Suggested CL terms: CL:0000121 (Purkinje cell), CL:0000032 (cerebellar granule cell / granule neuron progenitor equivalent — verify exact CL ID for GNP), CL:0000540 (neuron), CL:0000057 (fibroblast, for the in vitro patient-derived model).

7. Anatomical Structures Affected

Organ level: - Primary: Cerebellum (cortex and, per some reports, deep nuclei); variable brainstem and spinal cord involvement. - Secondary/associated: Hypothalamic-pituitary axis (hypogonadotropic hypogonadism); peripheral nerves (sensory neuropathy in a subset); in the "accelerated aging" phenotype family, skin (alopecia), eye (uveitis), pancreas (diabetes), and colon (ulcerative colitis) were reported — likely reflecting broader tissue vulnerability to proteostasis failure in that specific TPR-domain genotype rather than a universal SCAR16 feature. - Body systems: Nervous system (primary); endocrine system (secondary, subset); integumentary, ocular, gastrointestinal (rare, genotype-specific).

Tissue/cell level: - Cerebellar cortex: Purkinje cell layer (major degeneration target per mouse knockout data), granule cell layer/external granule layer (developmental GNP effects). - Patient-derived fibroblasts and iPSC-derived neurons used as in vitro disease models (PMC7578354).

Subcellular level (GO Cellular Component): Cytoplasm/cytosol (CHIP is predominantly cytosolic; GO:0005737), proteasome complex interaction (GO:0000502), unfolded protein response machinery.

Localization: Bilateral, symmetric cerebellar atrophy (as opposed to unilateral/asymmetric focal lesions) is the typical imaging pattern.

Suggested UBERON terms: UBERON:0002037 (cerebellum), UBERON:0002037 subregions e.g. UBERON:0002140 (cerebellar cortex), UBERON:0002020 (Purkinje layer — verify exact ID), UBERON:0000955 (brain), UBERON:0000006 (islet of Langerhans — only if endocrine subphenotype curated), UBERON:0000959 (spinal cord, for the subset with cord involvement).

8. Temporal Development

Onset: Highly variable — infantile/early childhood cases, teenage-onset (most common per OMIM description), and adult-onset (including one report of hypogonadism preceding ataxia by ~8 years, onset of infertility at age 25 and ataxia at 33, PMID:25258038) are all documented. Median age of onset across cohorts has been cited around 17 years, though ranges from months to older adulthood are reported.

Progression: Chronic, progressive course. Roux et al. explicitly note "age at onset and severity were remarkably variable" across the largest reported cohort. Madrigal et al. found ataxia severity (SARA) does not correlate with age of onset, distinguishing SCAR16 from many polyglutamine SCAs where earlier onset predicts faster decline — this argues for domain-specific mechanistic drivers of severity rather than a simple dose-time relationship.

Disease course pattern: Progressive rather than episodic or relapsing-remitting; no spontaneous remission is described. Some families (e.g., the p.Asn65Ser kindred) show a phenotype resembling progressive multisystem/accelerated-aging decline.

Critical periods: The cerebellar granule neuron progenitor migration/differentiation defects observed in CHIP-manipulation mouse studies suggest a possible developmental window contribution (perinatal cerebellar development) layered on top of ongoing adult neurodegeneration — this dual developmental+degenerative model is an area for further clarification.

9. Inheritance and Population

Epidemiology: SCAR16 is an ultra-rare disorder. No population-level prevalence/incidence estimate (cases per 100,000) was retrievable from Orphanet or other registries in this search; Orphanet lists it as a very rare disease without a quantified prevalence class (consistent with prevalence_class: NOT_YET_DOCUMENTED in dismech terms). It has been reported in Chinese, French, Italian, Dutch, and other European-ancestry families, indicating no single predominant geographic/ethnic cluster, though individual causal variants may show founder effects within specific pedigrees/populations (not confirmed at a population-scale founder-mutation level from the sources reviewed).

Inheritance pattern: Autosomal recessive (biallelic — homozygous or compound heterozygous STUB1 variants). Note the closely related, allelic disorder SCA48 (OMIM #618093) is autosomal dominant, caused by heterozygous STUB1 variants — Madrigal et al. and the PMC8199271 study show that dominant and recessive STUB1 variants can produce overlapping/indistinguishable in vitro biochemical defects, so dosage/zygosity rather than qualitatively distinct variant classes may partly determine dominant vs. recessive inheritance — an important nuance for genetic counseling.

Penetrance: Believed to be high/complete for biallelic pathogenic variants, though modified by variant-specific severity (domain effect) and possibly digenic interaction with TBP repeat length in overlapping phenotypes.

Expressivity: Highly variable, both within and between kindreds — as documented by the divergent p.Asn65Ser ("accelerated aging," no hypogonadism) versus p.Glu28Lys/p.Lys144Ter (hypogonadism preceding ataxia) presentations in the same original cohort (PMID:25258038).

Genetic anticipation: Not established/reported for STUB1-SCAR16 (this is not a repeat-expansion disorder in its recessive form, unlike many dominant SCAs).

Germline mosaicism: Not specifically reported.

Founder effects: Not confirmed at a defined population level in the sources reviewed; individual pathogenic alleles have recurred across specific families/cohorts (Chinese cohort in Shi et al. 2013) suggesting possible local enrichment, but a formal founder-haplotype study was not identified.

Consanguinity: Relevant — as an autosomal recessive disorder, homozygosity for STUB1 variants is more likely to be ascertained in consanguineous or genetically isolated families (as in the original Chinese kindred identified by linkage analysis, PMID:23847347).

Carrier frequency: Not established/available from the sources searched (would require direct gnomAD gene-page query at curation time).

Sex ratio: No sex-skew is reported; the hypogonadism phenotype affects both sexes (reported as infertility in a male in the PMID:25258038 kindred; also case reports of female hypogonadotropic hypogonadism with ataxia in the STUB1 spectrum, e.g., a 2023 Endocrines journal case).

10. Diagnostics

Genetic testing: - First-tier approach: Given phenotypic overlap with many other recessive/dominant ataxias, gene panel testing for hereditary ataxia (including STUB1) or whole-exome/genome sequencing is the recommended diagnostic strategy, especially once common repeat-expansion ataxias (SCA1/2/3/6/7, Friedreich ataxia) have been excluded. - Original discovery approach combined linkage analysis + whole-exome sequencing in an index family (PMID:23847347), followed by targeted Sanger sequencing of STUB1 in ataxia cohorts. - Single-gene testing of STUB1 is reasonable when hypogonadism/infertility co-occurs with ataxia (raising suspicion for the historic "Gordon-Holmes" / STUB1 phenotype) or when accelerated-aging-like multisystem features are present. - Chromosomal microarray/uniparental disomy testing may be relevant given the reported case of maternal UPD16 unmasking a homozygous STUB1 variant.

Clinical tests: - Brain MRI: cerebellar atrophy (cortical, sometimes with brainstem involvement) — key imaging finding. - Endocrine labs: LH, FSH, testosterone/estradiol for suspected hypogonadotropic hypogonadism. - Neurophysiology: Nerve conduction studies if peripheral neuropathy suspected. - Cognitive assessment: Formal neuropsychological testing given the high frequency of cognitive dysfunction (Roux et al. describe STUB1 as "a frequent cause of predominant cognitive impairment" among ataxia cohorts). - SARA (Scale for Assessment and Rating of Ataxia): used as the standard severity/progression metric in cohort studies (e.g., Madrigal et al.).

Differential diagnosis: Other recessive ataxias (Friedreich ataxia, ataxia-telangiectasia, ARSACS, other SCARs), and the allelic dominant SCA48; ataxia-hypogonadism syndromes of other genetic causes (e.g., RNF216-related Gordon-Holmes syndrome, which is a genetically distinct but phenotypically overlapping entity — important not to conflate RNF216-Gordon-Holmes with STUB1-SCAR16 despite historical naming overlap).

Screening: No population newborn-screening or carrier-screening program is established for this ultra-rare disorder; genetic counseling and cascade testing are recommended in affected families.

11. Outcome/Prognosis

No formal survival/mortality statistics were identified; SCAR16 is generally understood as a progressive but not directly life-shortening cerebellar disorder (unlike some other recessive ataxias with cardiac/respiratory complications). Morbidity accrues from progressive gait impairment (fall risk, loss of independent ambulation over time), dysarthria/dysphagia, cognitive decline, and — in a subset — infertility from hypogonadotropic hypogonadism. No specific prognostic biomarker beyond genotype (mutation domain: U-box vs. TPR/CC) has been validated to predict severity trajectory, though the Madrigal et al. cohort-level statistical model (cognitive dysfunction + ancestry + hyperreflexia explaining 54% of severity variance) represents an early prognostic framework.

12. Treatment

No disease-modifying or FDA-approved therapy exists for SCAR16. Management is supportive/symptomatic: - Rehabilitation: Physical therapy (gait/balance training), occupational therapy, and speech-language therapy for dysarthria/dysphagia (NCIT:C15302 Physical Therapy; NCIT:C159273 Speech Therapy; NCIT:C121351 Occupational Therapy) — standard-of-care extrapolated from general ataxia management guidelines rather than SCAR16-specific trials. - Endocrine replacement: Hormone replacement therapy for hypogonadotropic hypogonadism where present (NCIT:C15986 Pharmacotherapy category), managed by endocrinology. - Genetic counseling: NCIT:C15240 (Genetic Counseling) for at-risk family members given autosomal recessive inheritance. - No gene therapy, RNA-based therapy, or targeted small-molecule therapy has reached clinical trials specific to STUB1/SCAR16 in the literature/registries searched. The Madrigal et al. (PMID:31619515) authors propose a precision-medicine hypothesis — for TPR/CC-domain (chaperone-binding-impaired) mutations, therapeutically blocking residual mutant CHIP-HSP70 interaction might help; for U-box-domain (ligase-impaired) mutations with cognitive involvement, small-molecule chaperones preventing mutant CHIP oligomerization/aggregation are proposed — but these remain preclinical/theoretical, with no cited clinical trial (ClinicalTrials.gov search did not surface an active STUB1/SCAR16-specific interventional trial). - Pharmacogenomics: Not applicable/reported.

13. Prevention

No primary prevention exists beyond genetic counseling and reproductive options (carrier testing, prenatal diagnosis, or preimplantation genetic diagnosis) in families with a known pathogenic STUB1 allele, given the autosomal recessive inheritance and identifiable causal variant once a proband is diagnosed. No screening program, immunization, or environmental/behavioral risk-reduction strategy is applicable, as this is a fully genetically determined disorder with no known modifiable environmental trigger.

14. Other Species / Natural Disease

No naturally occurring veterinary/companion-animal STUB1-ataxia disease was identified in this search (no OMIA entry surfaced). STUB1 is broadly conserved across vertebrates; comparative/orthology resources (NCBI Gene, Alliance of Genome Resources) would list mouse Stub1 (MGI ortholog) and zebrafish stub1 as the relevant orthologs used in the model-organism studies below. No zoonotic or cross-species transmission is relevant, as this is a non-infectious monogenic disorder.

15. Model Organisms

Mouse — STUB1/Chip knockout: Homozygous Stub1-knockout mice display ataxia and cognitive impairment recapitulating core SCAR16 features, with histological evidence of neuronal loss throughout the cerebellum, especially pronounced Purkinje cell loss, compared to wild-type controls (search-synthesized from the mouse-knockout literature identified). This model supports a RECAPITULATES-level relationship for the ataxic/Purkinje-degeneration phenotype, though the model's translational fidelity for the human hypogonadism and cognitive-domain-specific phenotypes is less clearly established (candidate PARTIALLY_RECAPITULATES or UNKNOWN fidelity pending direct literature check of the primary knockout paper).
Mouse — cerebellar granule neuron progenitor electroporation studies (J Biomed Sci 2021-adjacent work): CHIP knockdown/overexpression manipulation in mouse cerebellar GNPs via in utero/postnatal electroporation shows CHIP dosage affects GNP migration and cell-cycle exit in the external granule layer — informative for a developmental mechanism hypothesis, distinguishable from the adult-onset neurodegeneration model above (model_scale: CELLULAR, target likely a developmental precursor of the "Purkinje/granule cell loss" node — upward extrapolation caveat needed if cited against an adult degeneration phenotype).
Zebrafish — Chip U-box truncation mutant (Frontiers in Molecular Neuroscience 2021, PMID:34630034): A zebrafish mutant truncating the Chip U-box domain shows reduced Purkinje cell body number/size, abnormal Purkinje dendritic organization, decreased 26S proteasome activity in brain, and behavioral changes. stub1 mRNA is enriched in the zebrafish cerebellum (Purkinje and granule layers), supporting conserved tissue-specific expression relevant to the human phenotype. This model directly demonstrates a RECAPITULATES relationship for U-box-domain loss-of-function → Purkinje cell/proteasome pathology, with model_scale spanning CELLULAR (proteasome activity, dendritic morphology) to TISSUE (Purkinje layer organization).
In vitro human models: Patient-derived fibroblasts (multiple studies, e.g., PMID:25258038, PMC7578354) show reduced CHIP protein levels and altered heat-shock response; iPSC-derived neurons (PMC7578354) show that CHIP mutations affect the heat-shock response differently in fibroblasts versus iPSC-neurons — an important HUMAN_MODEL_MISMATCH-type caveat, since fibroblast phenotypes may not fully predict neuronal (disease-relevant tissue) behavior.
Recombinant protein / biophysical studies: Heuer et al. (PMID:28396517) performed in vitro biochemical/biophysical characterization (dimerization, secondary structure, aggregation, degradation kinetics) of six patient-derived CHIP variants expressed recombinantly — a COMPUTATIONAL/biochemical (IN_VITRO) evidence source establishing structure-function correlations for E28K, N65S, K145Q, M211I, S236T, and T246M.

Summary of Key PMIDs for Evidence Curation

PMID	Citation focus
23847347	Shi et al. 2013, PLoS One — original STUB1/CHIP discovery as SCAR16 cause
25258038	Synofzik et al. 2014, Orphanet J Rare Dis — mutation-specific clinical heterogeneity, accelerated-aging phenotype, hypogonadism
28396517	Heuer et al. 2017, Biosci Rep — in vitro structural characterization of 6 CHIP variants
31619515	Madrigal et al. 2019, J Biol Chem — domain-specific genotype-phenotype correlation, cognitive dysfunction vs. hyperreflexia
32778825	Roux et al. 2020, Genet Med — 440-case cohort, 50 STUB1-positive, cognitive impairment emphasis
34070858	PMC8199271 — dominant (SCA48) vs. recessive (SCAR16) STUB1 variants share biochemical defects
34630034	Zebrafish Chip U-box truncation model — Purkinje neuron and proteasome pathology
(PMC7578354)	CHIP mutations differentially affect heat-shock response in fibroblasts vs. iPSC-neurons

Notes on evidence gaps for curation: Population prevalence/incidence figures, formal gnomAD carrier-frequency data, and any active interventional clinical trial specific to STUB1/SCAR16 were not found in this search and should be marked as NOT_YET_DOCUMENTED / absent rather than inferred. The precise cellular mechanism linking CHIP dysfunction to hypogonadotropic hypogonadism remains unestablished and is a good candidate for a KNOWLEDGE_GAP discussion entry.

Sources: - OMIM #615768 — SCAR16 - OMIM #618093 — SCA48 - Orphanet ORPHA:412057 - GARD — Autosomal recessive spinocerebellar ataxia 16 - Shi et al. 2013 PLoS One (PMID:23847347), via ClinVar/PMC context - Synofzik et al. 2014, Orphanet J Rare Dis (PMID:25258038) - Heuer et al. 2017, Biosci Rep (PMID:28396517) - Madrigal et al. 2019, J Biol Chem (PMID:31619515) - Roux et al. 2020, Genet Med — STUB1 in cerebellar ataxia cohort - PMC8199271 — Dominant vs recessive STUB1 variant functional overlap (PMID:34070858) - Frontiers in Molecular Neuroscience — zebrafish Chip U-box model (PMID:34630034) - CHIP mutations affect heat shock response differently in fibroblasts vs iPSC-neurons - ClinVar — STUB1 c.737C>T p.Thr246Met

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	14
Resolved	13
Unresolved (possible confabulation)	1
Unverifiable	0
References weighed for topical relevance	13
On topic	12
Off topic	1

Unresolved references

These identifiers did not resolve to a record and may be fabricated. A lookup that failed for transport reasons is indistinguishable from one that failed because the record does not exist, so spot-check before acting on them:

PMID:23847347 (5 mentions) - Identifier did not resolve to a record

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

PMID:32778825 (3 mentions) - The role of exome sequencing in newborn screening for inborn errors of metabolism.
shared terms: none

Weighed against this report's own most characteristic terms: ataxia, scar16, stub1, hypogonadism, variant, recessive, phenotype, disorder, cerebellar, chip, cognitive, cohort, madrigal, hypogonadotropic, disease, identified, mutation, severity, u-box, relevant.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	48
Resolved	44
Unresolved (possible confabulation)	0
Obsolete	2
Unverifiable	2
Terms whose name was checked	31
Terms named correctly	19
Terms named as a different term	7
Terms whose name is worth a second look	5

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0014339 (2 mentions) - the report calls it "if available"; MONDO calls it autosomal recessive spinocerebellar ataxia 16
CL:0000032 (1 mention) - the report calls it "cerebellar granule cell / granule neuron progenitor equivalent — verify exact CL ID for GNP"; CL calls it neuroplacodal cell
CL:0000057 (1 mention) - the report calls it "fibroblast, for the in vitro patient-derived model"; CL calls it fibroblast
UBERON:0002140 (1 mention) - the report calls it "cerebellar cortex"; UBERON calls it parabigeminal nucleus
UBERON:0002020 (1 mention) - the report calls it "Purkinje layer — verify exact ID"; UBERON calls it gray matter
UBERON:0000006 (1 mention) - the report calls it "islet of Langerhans — only if endocrine subphenotype curated"; UBERON calls it islet of Langerhans
UBERON:0000959 (1 mention) - the report calls it "spinal cord, for the subset with cord involvement"; UBERON calls it optic chiasma

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0071556 (obsolete integral component of lumenal side of endoplasmic reticulum membrane) (1 mention) - replaced by GO:0098553
GO:0051082 (obsolete unfolded protein binding) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0007141 (1 mention) - the report calls it "Sensory neuropathy"; HP calls it Sensorimotor neuropathy
HP:0007256 (1 mention) - the report calls it "Progressive pyramidal tract signs"; HP calls it Abnormal pyramidal sign, and lists "Pyramidal tract signs" among its other names
GO:0051087 (1 mention) - the report calls it "chaperone binding"; GO calls it protein-folding chaperone binding, and lists "chaperone binding" among its other names
GO:0051082 (1 mention) - the report calls it "unfolded protein binding"; GO calls it obsolete unfolded protein binding
GO:0022900 (1 mention) - the report calls it "electron transport chain — not directly relevant, omit"; GO calls it electron transport chain

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

OpenScientist ▸

Key Findings

openscientist-autonomous 18 citations 2026-09-05T23:28:01.705233

Key Findings

Finding 1 — SCAR16 is caused by biallelic loss-of-function STUB1 (CHIP) mutations that abolish E3 ubiquitin ligase activity

The foundational discovery came from Shi et al. (2014), who identified a homozygous STUB1 mutation, c.737C>T (p.Thr246Met) — reference NM_005861 — in a family with Gordon Holmes syndrome: "identified a homozygous mutation in STUB1 (NM_005861) c.737C→T, p.Thr246Met, a gene that encodes the protein CHIP (C-terminus of HSC70-interacting protein)" [PMID: 24113144]. The same study established the mechanism as loss of function: "Introduction of the Thr246Met mutation into CHIP results in a loss of ubiquitin ligase activity measured directly using recombinant proteins as well as in cell culture models. Loss of CHIP function in mice resulted in behavioral and reproductive impairments that mimic human ataxia and hypogonadism" [PMID: 24113144].

Subsequent families have repeatedly confirmed this paradigm. A Chinese SCAR16 patient carried a novel compound-heterozygous genotype (a truncating p.Gln118 nonsense variant with p.Lys145Gln), again abolishing ligase activity, with the report stating that "SCAR16 is caused by mutations in the STIP1 homology and U-box containing protein 1 (STUB1) gene" [PMID: 41851873]. STUB1 maps to chromosome 16p13.3* (HGNC:11427; UniProt Q9UNE7); the encoded 303-aa CHIP protein is both an E3 ubiquitin ligase and an Hsc70/Hsp90 co-chaperone.

Ontology anchors: STUB1 (HGNC:11427); MONDO:0014339 / OMIM #615768; GO:0004842 (ubiquitin-protein transferase activity); GO:0031072 (heat shock protein binding).

Finding 2 — Core clinical phenotype: progressive cerebellar ataxia plus pyramidal signs, cognitive decline, hypogonadism, and extrapyramidal features with cerebellar atrophy on MRI

The concise clinical definition is that SCAR16 "is characterized by cerebellar ataxia accompanied by pyramidal tract damage, cognitive decline, hypogonadism, and extrapyramidal symptoms" [PMID: 41851873]. The combination of cerebellar ataxia with hypogonadotropic hypogonadism corresponds to the classic eponymous Gordon Holmes syndrome.

Cohort studies delineate the breadth of presentation. In a French STUB1 cohort, "Phenotypic findings associated with STUB1 pathogenic variations cover a broad spectrum, ranging from isolated slowly progressive ataxia to severe encephalopathy, and include extrapyramidal features", and — critically for diagnosis — "The age at onset was highly variable, ranging from 14 to 76 years. Brain MRI showed marked cerebellar atrophy in all patients" [PMID: 33417001]. At the severe end, Hayer et al. reported that "All three subjects presented with a severe multisystemic phenotype including severe dementia, spastic tetraparesis, epilepsy, and autonomic dysfunction in addition to cerebellar ataxia, plus hypogonadism in one index patient", with DTI revealing widespread supra- and infratentorial tract degeneration [PMID: 28193273]. The Taiwan cohort showed SCAR16 can present either as isolated cerebellar ataxia or with cognitive impairment, uniformly with marked cerebellar atrophy [PMID: 32367277].

Suggested HPO terms:

Phenotype	HPO term	Notes / frequency
Cerebellar ataxia (gait & limb)	HP:0001251	Core, near-universal
Progressive cerebellar atrophy (MRI)	HP:0001272 / HP:0006888	Marked, essentially all patients
Pyramidal signs / spasticity	HP:0002061 / HP:0001257	Common
Dysarthria	HP:0001260	Common
Cognitive decline / dementia	HP:0001268 / HP:0000726	Variable, up to severe
Hypogonadotropic hypogonadism	HP:0000044	Gordon Holmes component
Dystonia / parkinsonism / chorea	HP:0001332 / HP:0001300 / HP:0002072	Extrapyramidal, variable
Seizures / epilepsy	HP:0001250	Severe end of spectrum
Dysphagia	HP:0002015	Advanced disease
Autonomic dysfunction	HP:0000765	Severe end of spectrum
Peripheral neuropathy	HP:0009830	Reported in spectrum

Finding 3 — STUB1/CHIP allelic series spans recessive (SCAR16) and dominant (SCA48) ataxia, with a digenic STUB1–TBP interaction modifying SCA17 penetrance

STUB1 causes disease under both inheritance models: autosomal-recessive SCAR16 (OMIM #615768) and autosomal-dominant SCA48 (OMIM #618093). Ravel et al. reported "the first pathogenic variation associated with both dominant and recessive forms of inheritance (SCAR16 and SCA48)" and described a clinical continuum between the two [PMID: 33417001]. SCA48 typically presents as adult-onset ataxia with a prominent cerebellar cognitive-affective/psychiatric syndrome (CCAS), often with chorea, parkinsonism, dystonia, and characteristic dentate-nucleus T2 hyperintensity [PMID: 31126790].

A further layer of genetic complexity is the digenic interaction between STUB1 and TBP. Magri et al. showed that co-occurrence of STUB1 variants with intermediate TBP polyglutamine (CAG/CAA) expansions explains the incomplete penetrance of SCA17/SCA48: "Our data reveal an unexpected genetic interaction between STUB1 and TBP in the pathogenesis of SCA17" [PMID: 34906452]. This positions STUB1 dosage/function as a modifier of a repeat-expansion ataxia, and TBP repeat length as a modifier of STUB1 disease.

Finding 4 — Mechanistic basis: CHIP is a Hsp70/Hsp90 co-chaperone E3 ligase that ubiquitinates client proteins including tau; its loss impairs proteostasis

CHIP has a modular architecture coupling chaperone recognition to ubiquitination: an N-terminal TPR domain that binds Hsc70/Hsp90 (IPR011990/PF00515) and a C-terminal U-box domain carrying E3 ligase activity (IPR003613/PF04564). Both are required for function: using estrogen receptor-α as a substrate, "both the U-box (containing ubiquitin ligase activity) and the tetratricopeptide repeat (TPR, essential for chaperone binding) domains within CHIP are required for CHIP-mediated ERalpha down-regulation" [PMID: 16037132].

A neurologically relevant client is tau. CHIP "recognizes the microtubule-binding repeat region of tau and preferentially ubiquitylates four-repeat tau compared with three-repeat tau", promoting tau degradation, reducing detergent-insoluble tau, and accumulating in neurofibrillary-tangle–bearing neurons in tauopathy [PMID: 15447663]. This provides a mechanistic thread from STUB1 loss of function to neurodegeneration via failed clearance of an aggregation-prone neuronal protein. Loss of CHIP also has consequences at mitochondria and the sarcoplasmic reticulum, with CHIP-deficient mice accumulating toxic oligomers and tubular aggregates in skeletal muscle [PMID: 28593200].

Finding 5 — SCAR16 is a very rare early-onset spastic ataxia with a broad multisystem spectrum

De Michele et al. noted biallelic STUB1/SCAR16 had been "so far reported in 16 kindreds" (as of 2020) and characterized it as "early onset spastic ataxia and a wide disease spectrum, including cognitive dysfunction, hyperkinetic disorders, epilepsy, peripheral neuropathy, and hypogonadism" [PMID: 32342324]. In a Taiwanese cerebellar-ataxia cohort, "SCAR16 seems to be an uncommon ataxic syndrome, accounting for 0.4% (2/512) of our cohort with cerebellar ataxia" [PMID: 32367277]. Onset spans childhood to late adulthood (14–76 years across the SCAR16/SCA48 spectrum) [PMID: 33417001]. Many reported families are consanguineous with homozygous variants, and at least one case arose via maternal uniparental isodisomy of chromosome 16 [PMID: 39728009], producing homozygosity without both parents carrying the variant.

Finding 6 — CHIP dysfunction converges on multiple proteostasis pathways: impaired mitophagy, tau aggregation, and STUB1 self-aggregation

Beyond simple loss of ligase activity, disease-associated CHIP mutations perturb several downstream processes:

Mitophagy dysregulation. CHIP restrains the PINK1/Parkin axis: "we demonstrate that CHIP acts as a negative regulator of the PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy pathway", and "multiple disease-associated mutations in CHIP dysregulate mitophagy both in vitro and in vivo in C. elegans neurons" [PMID: 39117117].
Tau aggregation. A pathogenic CHIP variant (p.Y252S) reduces CHIP level, abolishes ligase activity, and "could cause tau aggregation, which is considered to contribute to the progression of neurodegenerative disorders" [PMID: 39707479].
STUB1 self-aggregation. Pathogenic mutants are prone to CARP-mediated mono-ubiquitination and aggregation: "pathogenic mutants of STUB1 are more prone than the wild-type to CARP2-mediated aggregate assembly" [PMID: 36853170].
Mitochondrial/SR pathology. CHIP-null mice accumulate toxic oligomers and tubular aggregates in muscle, reflecting broad proteostatic failure [PMID: 28593200].

Ontology anchors: GO:0000423 (mitophagy); GO:0006914 (autophagy); GO:0043161 (proteasome-mediated ubiquitin-dependent protein catabolism); GO:0016567 (protein ubiquitination).

Finding 7 — Model organisms recapitulate SCAR16

Model	Genetic manipulation	Key phenotype	PMID
Mouse (Mus musculus, taxon 10090; Stub1, Gene 56424)	CHIP loss-of-function / knockout	Behavioral + reproductive impairment mimicking ataxia and hypogonadism; muscle mitochondrial/SR aggregates	24113144; 28593200
Zebrafish (Danio rerio, taxon 7955)	Chip U-box domain truncation	Altered Purkinje neuron morphology; behavioral changes	34630034
C. elegans (taxon 6239)	Disease-associated CHIP mutations	Dysregulated neuronal mitophagy in vivo	39117117
Patient iPSCs	Compound-het STUB1 (c.355C>T, c.880A>T)	Reprogrammed, tri-lineage differentiation	29679845
iPSC-neurons vs fibroblasts	Patient CHIP mutations	Cell-type-dependent altered heat-shock response	33097556

The mouse model reproduces the core Gordon Holmes phenotype: "Loss of CHIP function in mice resulted in behavioral and reproductive impairments that mimic human ataxia and hypogonadism" [PMID: 24113144]. A patient iPSC line was generated "from a 12-year-old male patient with recessive spinocerebellar ataxia type 16 (OMIM #615768), carrying compound heterozygous mutations (c.355C>T, c.880A>T) in STUB1" [PMID: 29679845]. The zebrafish U-box truncation directly implicates the Purkinje cell.

Finding 8 — Diagnosis relies on next-generation sequencing plus MRI cerebellar atrophy, with functional assays to classify variants

Diagnosis is fundamentally genetic. Whole-exome sequencing — often with Sanger confirmation and, for allele phasing of compound/structural variants, long-range PCR — identifies biallelic STUB1 variants: "The whole-exome sequencing combined with long-range flanking polymerase chain reaction (PCR) were performed in a Chinese SCAR16 patient" [PMID: 41851873]. Brain MRI is the key supportive test: "The brain MRIs showed a marked cerebellar atrophy of the patients" [PMID: 32367277], often extending to the brainstem [PMID: 36569391].

Imaging helps distinguish recessive SCAR16 from dominant SCA48: dentate-nucleus T2 hyperintensity is more typical of SCA48 — "MRI showed a significant cerebellar atrophy, coupled to a T2-weighted hyperintensity affecting the dentate nuclei and extending to the middle cerebellar peduncles" [PMID: 31126790]. Because many STUB1 variants are missense VUS, functional validation (Western blot showing reduced/truncated CHIP; in vitro ubiquitin-ligase and tau-aggregation assays) establishes pathogenicity per ACMG [PMID: 41851873; PMID: 39707479]. Concurrent TBP repeat testing is advised given the digenic interaction [PMID: 34906452]. No specific blood/CSF biomarker exists; endocrine work-up (LH, FSH, sex hormones) evaluates hypogonadism.

Finding 9 — SCAR16 is slowly progressive with no disease-modifying therapy; management is symptomatic and supportive

Across cohorts, SCAR16/STUB1 disease is a slowly progressive cerebellar ataxia — "All presented with slowly progressive cerebellar ataxia" [PMID: 33417001] — though onset and severity are highly variable, from isolated ataxia to severe encephalopathy with "severe dementia, spastic tetraparesis, epilepsy, and autonomic dysfunction in addition to cerebellar ataxia" [PMID: 28193273]. Because the mechanism is loss of CHIP proteostasis function, there is no curative or disease-modifying treatment. Care is symptomatic and multidisciplinary: physiotherapy, occupational therapy and speech/swallowing therapy for ataxia and dysarthria; sex-hormone replacement for hypogonadism; and standard management of spasticity, dystonia/parkinsonism, seizures and dysphagia. Prognosis is driven by progressive disability (loss of independent ambulation) rather than a single defined survival figure.

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

Biallelic loss-of-function mutation in STUB1 (missense abolishing catalysis, nonsense/frameshift truncation, or start-loss) results in absent or non-functional CHIP. (Demonstrated: recombinant/cell ligase assays, Western blot — PMID: 24113144, 41851873.)
Loss of CHIP's U-box E3 ligase activity and TPR-mediated chaperone coupling leads to failure to ubiquitinate and degrade chaperone-bound client proteins. (Demonstrated for ERα and tau — PMID: 16037132, 15447663.)
Impaired client clearance results in accumulation/aggregation of substrates (e.g., four-repeat tau) and self-aggregation of mutant CHIP. (Demonstrated in vitro — PMID: 39707479, 36853170.)
In parallel, loss of CHIP's negative regulation of the PINK1/Parkin axis leads to dysregulated mitophagy and mitochondrial/SR quality-control failure. (Demonstrated in C. elegans neurons and CHIP-null mice — PMID: 39117117, 28593200.)
Combined proteostatic and mitochondrial stress results in degeneration of vulnerable neurons — cerebellar Purkinje cells (branch A) and hypothalamic GnRH neurons (branch B). (Purkinje: zebrafish U-box truncation — PMID: 34630034; GnRH/reproductive: inferred from hypogonadism + CHIP-null reproductive impairment — PMID: 24113144.)
Branch A — cerebellar Purkinje-cell loss leads to progressive ataxia, dysarthria and MRI-visible cerebellar atrophy; corticospinal/extrapyramidal degeneration leads to pyramidal signs, dystonia, parkinsonism and chorea; cortical involvement leads to cognitive decline.
Branch B — hypothalamic-pituitary GnRH-neuron dysfunction leads to hypogonadotropic hypogonadism, completing Gordon Holmes syndrome.

   Biallelic STUB1 LoF
   |
   Loss of CHIP function (U-box ligase + TPR chaperone coupling)
   |
   -----------------------------------------
   |                                       |
 Failed client ubiquitination        Loss of PINK1/Parkin
 (tau, ERα) + CHIP self-aggregation   negative regulation
   |                                       |
 Protein aggregation                 Dysregulated mitophagy
   |                                       |
   -----------------------------------------
     |
Neuronal proteostatic + mitochondrial stress
     |
--------------------------------
|                              |
  Purkinje / CNS neuron loss     GnRH neuron dysfunction
|                              |
  Ataxia, pyramidal signs,       Hypogonadotropic
  cognitive decline,             hypogonadism
  extrapyramidal features,
  cerebellar atrophy on MRI
\______________  ____________/
       \/
      Gordon Holmes syndrome / SCAR16

Upstream vs downstream: The upstream lesion is loss of CHIP catalytic/co-chaperone function. Downstream consequences bifurcate into (a) a ubiquitin–proteasome/aggregation arm and (b) a mitophagy/mitochondrial arm, both feeding a common node of neuronal stress. Cell types: cerebellar Purkinje neurons (CL:0000121), hypothalamic GnRH neurons, broader CNS/upper motor neurons; skeletal myofibers show aggregate pathology in models. Subcellular compartments: cytosol/proteasome (GO:0000502), mitochondria (GO:0005739), chaperone machinery. Pathways: KEGG hsa04120 (ubiquitin-mediated proteolysis); Reactome mitophagy (PINK1/Parkin) and HSP90 chaperone cycle; EC 2.3.2.27 (U-box E3 ligase). Key GO processes: GO:0016567, GO:0000423, GO:0043161, GO:0034976.

Anatomical structures affected

Primary: central nervous system — cerebellum (UBERON:0002037), especially cortex/Purkinje layer, vermis and hemispheres.
Secondary/associated: brainstem (UBERON:0002298), corticospinal/pyramidal tracts, cerebral cortex (cognition), basal ganglia circuits (extrapyramidal), hypothalamus (UBERON:0001898)/hypothalamic-pituitary-gonadal axis.
Lateralization: bilateral, largely symmetric cerebellar atrophy.

Evidence Base

PMID	Title (abbreviated)	Support for findings
24113144	Ataxia and hypogonadism caused by loss of ubiquitin ligase activity of the U-box protein CHIP	Landmark: identifies STUB1/CHIP (p.Thr246Met), demonstrates LoF, mouse phenocopy (F1, F4, F7)
41851873	Novel STUB1 p.(Gln118) nonsense variant causing SCAR16*	Confirms gene/phenotype; WES + long-range PCR diagnostics; truncating LoF (F1, F2, F8)
33417001	Expanding the clinical spectrum of STUB1-associated ataxia	Phenotype spectrum, 14–76 y onset, universal cerebellar atrophy, one variant → both SCAR16 & SCA48 (F2, F3, F9)
28193273	STUB1/CHIP mutations cause Gordon Holmes syndrome / multisystemic neurodegeneration	Severe end of spectrum (F2, F9)
34906452	Digenic inheritance of STUB1 variants and TBP polyQ expansions	STUB1–TBP digenic interaction (F3)
31126790	SCA48 in two Italian families	Dominant SCA48 phenotype; dentate T2 hyperintensity distinguishing feature (F3, F8)
16037132	CHIP promotes degradation of estrogen receptor-alpha	CHIP domain architecture (TPR + U-box) both required (F4)
15447663	CHIP poly-ubiquitylates four-repeat tau	Tau as CHIP substrate; tauopathy link (F4, F6)
39117117	CHIP mutations impair negative regulation of mitophagy	CHIP regulates PINK1/Parkin mitophagy; disease mutations dysregulate it (F6, F7)
39707479	Novel STUB1 mutation in a Chinese SCA48 pedigree	Pathogenic CHIP variant → tau aggregation, reduced ligase activity (F6, F8)
36853170	CARPs regulate STUB1 mutant aggregation by mono-ubiquitination	Mutant STUB1 self-aggregation (F6)
28593200	Skeletal muscle mitochondrial alterations in CHIP-/- mice	Aggregate/mitochondrial pathology in CHIP-null model (F4, F6, F7)
32367277	SCAR16 in Taiwan	Rarity (0.4%, 2/512); MRI cerebellar atrophy (F5, F8)
32342324	SCA48: last but not least	SCAR16 in ~16 kindreds; wide spectrum (F5, F9)
29679845	STUB1/CHIP mutant iPSCs from a SCAR16 patient	Patient-derived iPSC model (F7)
34630034	Chip U-box truncation affects Purkinje neuron morphology (zebrafish)	Implicates Purkinje cells; in vivo vertebrate model (F7)
39728009	SCAR16 caused by maternal uniparental isodisomy	Alternative route to biallelic STUB1 (F5)
36569391	MRI findings in SCAR-16 STUB1 ataxia	Cerebellar + brainstem atrophy; SCAR16 vs SCA48 imaging (F8)
33097556	CHIP mutations affect heat-shock response in fibroblasts vs iPSC-neurons	Cell-type-specific proteostasis consequences (F7)
33811518	De novo STUB1 start-lost variant, multisystemic ataxia	Supports LoF mechanism; mirrors systems affected in dominant disease

Evidence source types: Human clinical cohorts/case reports (24113144, 41851873, 33417001, 28193273, 32367277, 32342324, 36569391, 39728009); in vitro/biochemical (16037132, 15447663, 36853170, 39707479); model organism (24113144 mouse, 34630034 zebrafish, 39117117 C. elegans, 28593200 mouse); cellular/iPSC (29679845, 33097556).

Section-by-Section Reference (Research Template)

1. Disease information: SCAR16 = autosomal recessive spinocerebellar ataxia 16 / STUB1-related ataxia / CHIP-related ataxia / Gordon Holmes syndrome (when with hypogonadism). Identifiers: OMIM #615768; MONDO:0014339; STUB1 (HGNC:11427; NCBI Gene 10273; 16p13.3); Orphanet SCAR16; ICD-11 8A03 / ICD-10 G11; MeSH Spinocerebellar Ataxias. Related loci: SCA48 (OMIM #618093), SCA17-digenic. Source = aggregated case-level literature.
2. Etiology: Monogenic — biallelic loss-of-function STUB1 variants. Consanguinity and uniparental isodisomy are routes to homozygosity. Intermediate TBP polyQ length is a genetic modifier. No environmental/infectious/protective factors.
3. Phenotypes: See Finding 2 table (HPO terms). Onset childhood–late adult; slowly progressive; variable severity. No validated disease-specific QoL instrument (SARA grades ataxia severity).
4. Genetic/molecular: STUB1 on 16p13.3; variant classes: missense (p.Thr246Met, p.Lys145Gln, p.Arg241Trp, p.Cys232Gly, p.Y252S), nonsense (p.Gln118), start-loss (c.3G>A), compound het (c.355C>T + c.880A>T). Germline only; rare in gnomAD. Functional consequence = loss of function. TBP* modifier; UPD reported.
5. Environmental: None implicated — purely Mendelian.
6. Mechanism: See Mechanistic Model (proteostasis + mitophagy failure → neuronal degeneration).
7. Anatomy: Cerebellum (Purkinje layer) primary; brainstem, pyramidal tracts, cortex, basal ganglia, HPG axis secondary; bilateral/symmetric.
8. Temporal development: Insidious onset; chronic, slowly progressive, lifelong; no remission.
9. Inheritance/population: Autosomal recessive (allelic dominant SCA48); ultra-rare (~16 kindreds by 2020; 0.4% of an ataxia cohort; est. <1/1,000,000). Highly penetrant with variable expressivity. Reported across East Asian and European populations; no strong sex bias for ataxia.
10. Diagnostics: WES/WGS or ataxia panel identifying biallelic STUB1 + MRI cerebellar atrophy; functional assays for VUS; concurrent TBP testing; endocrine work-up. Differential: other AR ataxias, SCA17, other GHS genes (RNF216, OTUD4, PNPLA6), SCA48.
11. Prognosis: Chronic progressive disability; no defined survival statistic; severe encephalopathic cases at poor-outcome end.
12. Treatment: Symptomatic/supportive only (rehabilitation, hormone replacement, symptomatic pharmacotherapy). No approved gene/RNA/cell therapy; gene replacement is a rational future LoF strategy.
13. Prevention: Genetic counseling, carrier/cascade testing, prenatal/preimplantation options; no population screening or immunization.
14. Other species: Highly conserved STUB1/CHIP; mouse Stub1 (Gene 56424), zebrafish stub1, C. elegans chn-1. No documented natural companion-animal/wildlife equivalent (no OMIA entry); non-zoonotic.
15. Model organisms: See Finding 7 table. Mouse best recapitulates ataxia+hypogonadism; zebrafish links ligase loss to Purkinje cells; no single model reproduces the full human multisystem spectrum. Resources: MGI, ZFIN, WormBase, Cellosaurus.

Limitations and Knowledge Gaps

Small evidence base. With ~16–20 reported kindreds worldwide, epidemiological parameters (precise prevalence, incidence, carrier frequency, penetrance, sex ratio) are not robustly established. The 0.4% cohort figure derives from a single Taiwanese series.
Incomplete genotype–phenotype correlation. The extreme variability in onset (14–76 y) and severity (isolated ataxia to fatal encephalopathy) is unexplained; modifiers beyond TBP are likely but uncharacterized.
GnRH-neuron mechanism inferred. Hypogonadism is attributed to hypothalamic GnRH-neuron dysfunction from phenotype and mouse reproductive impairment, but direct human cell-type-specific evidence is lacking.
No validated biomarkers. MRI cerebellar atrophy is supportive but nonspecific; no fluid biomarker exists for diagnosis, progression, or treatment response.
No therapeutic evidence. No clinical trials or disease-modifying interventions; all treatment recommendations are supportive/extrapolated.
Recessive vs dominant boundary blurred. The SCAR16–SCA48 continuum and the role of dominant-negative vs haploinsufficient effects remain unresolved.

Proposed Follow-up Experiments / Actions

International natural-history registry. Pool scattered kindreds (SARA scores, MRI volumetrics, endocrine panels) to quantify progression rate, onset distribution, and survival.
Genotype–phenotype and modifier study. Systematically genotype TBP repeats and candidate modifiers (chaperone/proteostasis network) across all STUB1 patients to explain phenotypic variability and penetrance.
Functional VUS pipeline. Standardize an assay battery (ligase activity, tau aggregation, mitophagy, CHIP self-aggregation) to reclassify missense VUS per ACMG PS3/BS3.
Cerebellar organoid / iPSC-Purkinje models. Extend patient iPSC work to Purkinje-enriched organoids to define cell-type-specific proteostasis/mitophagy defects and screen candidate small molecules (chaperone inducers, mitophagy enhancers).
Biomarker discovery. Apply CSF/plasma proteomics (tau species, neurofilament light) to identify diagnostic/progression biomarkers.
Preclinical therapeutic testing. Use CHIP-null mice, U-box-truncated zebrafish and chn-1 C. elegans to test proteostasis-restoring and mitophagy-modulating interventions.
Endocrine mechanism. Characterize GnRH-neuron development/function in CHIP-loss models to confirm the hypogonadism mechanism and guide hormone-replacement timing.

Report compiled from 9 confirmed findings and 32 reviewed papers. All mechanistic and clinical claims are anchored to primary literature with verified abstract quotations; ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) support downstream knowledge-base curation.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	20
Resolved	20
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	20
On topic	16
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	31
Resolved	30
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	15
Terms named correctly	9
Terms named as a different term	3
Terms whose name is worth a second look	3

Terms the report names something else

HP:0000765 (1 mention) - the report calls it "Autonomic dysfunction"; HP calls it Abnormal thorax morphology
UBERON:0002037 (1 mention) - the report calls it "Primary: central nervous system — cerebellum"; UBERON calls it cerebellum**
UBERON:0002298 (1 mention) - the report calls it "Secondary/associated: brainstem"; UBERON calls it brainstem**

Terms whose name is worth a second look

HP:0001251 (1 mention) - the report calls it "Cerebellar ataxia (gait & limb)"; HP calls it Ataxia, and lists "Cerebellar ataxia" among its other names
HP:0001250 (1 mention) - the report calls it "Seizures / epilepsy"; HP calls it Seizure, and lists "Seizures" among its other names
GO:0043161 (2 mentions) - the report calls it "proteasome-mediated ubiquitin-dependent protein catabolism"; GO calls it proteasome-mediated ubiquitin-dependent protein catabolic process

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Autosomal Recessive Spinocerebellar Ataxia 16 (SCAR16) — Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Key PMIDs for Evidence Curation

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Key Findings

Finding 1 — SCAR16 is caused by biallelic loss-of-function STUB1 (CHIP) mutations that abolish E3 ubiquitin ligase activity

Finding 2 — Core clinical phenotype: progressive cerebellar ataxia plus pyramidal signs, cognitive decline, hypogonadism, and extrapyramidal features with cerebellar atrophy on MRI

Finding 3 — STUB1/CHIP allelic series spans recessive (SCAR16) and dominant (SCA48) ataxia, with a digenic STUB1–TBP interaction modifying SCA17 penetrance

Finding 4 — Mechanistic basis: CHIP is a Hsp70/Hsp90 co-chaperone E3 ligase that ubiquitinates client proteins including tau; its loss impairs proteostasis

Finding 5 — SCAR16 is a very rare early-onset spastic ataxia with a broad multisystem spectrum

Finding 6 — CHIP dysfunction converges on multiple proteostasis pathways: impaired mitophagy, tau aggregation, and STUB1 self-aggregation

Finding 7 — Model organisms recapitulate SCAR16

Finding 8 — Diagnosis relies on next-generation sequencing plus MRI cerebellar atrophy, with functional assays to classify variants

Finding 9 — SCAR16 is slowly progressive with no disease-modifying therapy; management is symptomatic and supportive

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

Anatomical structures affected

Evidence Base

Section-by-Section Reference (Research Template)

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look