Ataxia-Telangiectasia-Like Disorder 2

Mendelian MONDO:0014399 Pathograph 8 Show in embeddings browser DNA Repair Disorder Progeroid Syndrome

Ataxia-telangiectasia-like disorder 2, better known in the molecular literature as PCNA-associated DNA repair disorder (PARD), is an autosomal recessive syndrome of short stature, sensorineural hearing loss, premature aging, cutaneous and conjunctival telangiectasia, progressive neurodegeneration with cerebellar atrophy, and cutaneous photosensitivity. It is caused by biallelic hypomorphic variants in PCNA, the sliding clamp that tethers the enzymes of DNA replication and repair to the template. The disorder exists only because the alleles are hypomorphic, and this is not a throwaway observation about severity. PCNA is essential; an allele that abolished its function would not be compatible with life, so the mutational window that can produce a viable human phenotype is narrow. Everything about the entry follows from that constraint - the founder origin of the first-described allele in an Amish pedigree, the small number of families, and the fact that basal DNA replication is essentially intact while the damage response is not. Two causal alleles are now described and they do not share a molecular mechanism. The original p.Ser228Ile substitution reshapes PCNA's partner-binding pocket and impairs interaction with a long list of client proteins, including flap endonuclease 1 and DNA ligase 1. The later p.Cys148Ser substitution leaves the structure and partner affinity looking like wild type. What the two share is a thermostability defect, and cells carrying the C148S allele have less PCNA on chromatin and show temperature-dependent phenotypes - which points at the amount of functional clamp available, rather than any one lost interaction, as the variable the disease actually tracks. That convergence is the most interesting thing in the entry and is curated as an explicit alternative mechanistic hypothesis rather than folded into a single chain. The name is a clinical description that has aged badly. The phenotype resembles ataxia-telangiectasia enough to have been labelled after it, but the mechanism is nucleotide-excision-repair-like photosensitivity rather than the double-strand-break signalling defect of ATM or MRE11 disease, and the "2" positions it as a sibling of MRE11-related ATLD1 which it does not mechanistically resemble.

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1
Mappings
1
Inheritance
4
Pathophys.
17
Phenotypes
2
Hypotheses
4
Gaps
8
Pathograph
1
Genes
3
Differentials
13
References
1
Deep Research
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Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE NEUROLOGIC
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Mappings

MONDO
MONDO:0014399 ataxia-telangiectasia-like disorder 2
skos:exactMatch MONDO
The dismech entry and the MONDO class denote the same entity: the PCNA-related recessive DNA repair disorder. The molecular literature calls it PARD, which is recorded as a synonym rather than as a separate concept.
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Inheritance

1
Autosomal recessive HP:0000007
Autosomal recessive. Both described alleles are homozygous in affected individuals, and the first was identified by homozygosity mapping in a consanguineous founder community, which is the ascertainment route that makes ultra-rare recessive alleles findable at all.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT Human Clinical
"Here, we describe a syndrome in which the cardinal clinical features include short stature, hearing loss, premature aging, telangiectasia, neurodegeneration, and photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence alteration of the proliferating cell nuclear antigen (PCNA)."
States the homozygous genotype of the affected individuals.
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Mechanistic Hypotheses

2
Disease follows from specific lost PCNA client interactions
lost_client_interactions CANONICAL
Evidence balance 1 support
The account that came with the founding report. The p.Ser228Ile substitution alters the partner-binding pocket, PCNA's interactions with flap endonuclease 1, DNA ligase 1 and a long list of other PIP-box clients are impaired, and the resulting failures of repair and of Okazaki-fragment maturation produce the phenotype. It explains the photosensitivity and the UV phenotypes of patient cells directly.
Pathograph links
Biallelic Hypomorphic PCNA Variant -> Impaired PCNA Client Protein Binding DIRECT For the S228I allele, the substitution reshapes the interdomain connecting loop and the binding pocket that PIP-box clients dock into.
Impaired PCNA Client Protein Binding -> Defective DNA Damage Response DIRECT Losing the docking of repair and Okazaki-maturation enzymes onto the clamp is the route from the binding defect to a failure of repair.
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT In Vitro
"The p.Ser228Ile change also profoundly altered PCNA's interaction with Flap endonuclease 1 and DNA Ligase 1, DNA metabolism enzymes."
Reports the interaction defect this hypothesis is built on.
Disease follows from a reduced pool of functional PCNA
reduced_functional_clamp_pool EMERGING
Evidence balance 2 support 1 refute
The account that the second allele forces. p.Cys148Ser causes the same disease with wild-type-like structure and wild-type-like partner affinity, so lost client binding cannot be the common cause. What both alleles do share is reduced thermostability, and C148S patient cells carry less PCNA on chromatin and behave differently at different temperatures. On this reading the operative variable is how much functional clamp is available, and the S228I interaction defects are one route to that rather than the mechanism itself.
Pathograph links
Biallelic Hypomorphic PCNA Variant -> Reduced PCNA Thermostability DIRECT Both described alleles destabilise the trimer, which is the one molecular property they have in common.
Reduced PCNA Thermostability -> Defective DNA Damage Response INDIRECT KNOWN INTERMEDIATES Less functional clamp on chromatin means fewer sites at which repair enzymes can be positioned, independently of any change in binding affinity.
Show evidence (3 references)
PMID:36990216 SUPPORT DIRECT In Vitro
"The stability defect of both PARD variants indicates that PCNA levels are likely an important driver of PARD disease."
States the hypothesis in the authors' own terms, and note their own hedge - "likely an important driver", not "the cause" - which is why this is EMERGING and not CANONICAL.
PMID:36990216 REFUTE DIRECT In Vitro
"Unlike PCNA-S228I, PCNA-C148S has WT-like structure and affinity toward partners."
Recorded as REFUTE against the lost-client-interaction hypothesis as a complete account. A second allele causing the same disease without the interaction defect is the observation that makes the canonical mechanism insufficient.
PMID:37511614 SUPPORT DIRECT In Vitro
"Incubation time dependent FRET measurements indicated no effect on PCNAC148S-p15 affinity, but on PCNA stability."
An independent replication of the C148S result by a different group using different methods (FRET, intrinsic tryptophan fluorescence, differential scanning fluorimetry and asymmetrical flow field-flow fractionation), and the reason this hypothesis rests on more than one laboratory's assay. It separates the two axes cleanly: partner affinity intact, stability not.
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Discussions and Knowledge Gaps

4
PCNA is required in every dividing cell. Why is a hypomorphic PCNA allele a neurodegenerative disease rather than a proliferative or a cancer-predisposition one?
KNOWLEDGE GAP why_the_phenotype_is_neurological
Attached to
pathophysiology#Defective DNA Damage Response phenotypes#
This is the question the pathograph does not answer. The chain runs from the allele to a repair defect that is demonstrable in patient fibroblasts, and then to a phenotype that is overwhelmingly cerebellar and neurodevelopmental. Nothing in the sources cited here explains the tissue selectivity. A candidate exists and is worth recording so that it can be tested rather than assumed: global-genome nucleotide excision repair is constitutively weaker in neurons and astrocytes than in fibroblasts, and the amount of PCNA recruited to UV-damage sites is correspondingly lower in those cells. If neural cells already operate near the lower limit of what the pathway can deliver, a hypomorphic clamp would bite there first while dividing tissues absorb it. The measurement supporting that is rat primary culture on wild-type cells, so it is a hypothesis about the general biology and not an observation about this disease. Two things would move it. A patient-derived neural model, of which none is reported here, and a comparison of chromatin-bound PCNA between patient neural cells and patient fibroblasts, which is measurable with the assay the founding reports already use.
Show evidence (2 references)
PMID:17236820 SUPPORT INDIRECT Model Organism
"The results demonstrate that both neurons and astrocytes have significantly lower NER capabilities than fibroblasts."
The candidate explanation for the tissue selectivity. INDIRECT and MODEL_ORGANISM: rat primary cultures of wild-type cells, so it establishes a baseline difference between cell types rather than anything about this disease.
PMID:17236820 SUPPORT INDIRECT Model Organism
"That result was consistent with the finding that levels of an NER-related protein (proliferating cell nuclear antigen, PCNA) recruited at the localized UV-damage sites were lower in neurons and in astrocytes than in fibroblasts."
Curated separately because it is the part that names PCNA specifically, which is what makes the candidate relevant to this disease rather than to NER disorders generally.
DNMT1 is among the PIP-box clients whose binding is impaired. Does ATLD2 carry a maintenance-methylation defect, and has anyone looked?
KNOWLEDGE GAP untested_epigenetic_branch
Attached to
pathophysiology#Impaired PCNA Client Protein Binding
The client-binding node records that DNMT1 is affected alongside the repair enzymes, and DNMT1 is how CpG methylation patterns survive replication. If clamp-dependent loading of DNMT1 is impaired in patient cells, the disease would have an epigenetic arm in addition to a repair arm, which would be a different kind of disease from the one this entry describes. The supporting biology is established outside this disease: DNMT1 is targeted to replication sites through a PCNA-binding domain, with a second PCNA-independent route through UHRF1/Np95 binding hemimethylated DNA. Two routes matter here, because a defect in the PCNA-dependent one need not abolish maintenance methylation - which is a reason the branch might be real and still hard to see. No source cited here reports methylation in ATLD2 patient cells, so this is an untested branch and not a suppressed finding. It is recorded rather than modelled: putting a methylation node in the pathograph would assert a claim nobody has made.
Show evidence (2 references)
PMID:23535145 SUPPORT INDIRECT In Vitro
"Two subdomains, the proliferating cell nuclear antigen (PCNA)-binding domain (PBD) and the targeting sequence (TS) domain, target Dnmt1 to the replication sites in S phase."
Establishes the PCNA-dependent route the gap is about, and that it is one of two. Mouse somatic cells and wild-type PCNA, so it says nothing about the disease variant.
PMID:17994007 SUPPORT INDIRECT Model Organism
"Np95 forms complexes with Dnmt1 and mediates the loading of Dnmt1 to replicating heterochromatic regions."
The parallel PCNA-independent loading route, and the reason a PCNA-side defect would not necessarily abolish maintenance methylation. Recorded because it bears on how hard the branch would be to detect, not because it supports the branch existing.
Do the two causal PCNA alleles produce the same disease by the same route, or by two different routes that happen to converge on the clinical phenotype?
KNOWLEDGE GAP allele_specific_mechanism
Attached to
pathophysiology#Impaired PCNA Client Protein Binding pathophysiology#Reduced PCNA Thermostability mechanistic_hypotheses#reduced_functional_clamp_pool
p.Ser228Ile impairs client binding across most PIP-box partners; p.Cys148Ser has wild-type-like structure and wild-type-like partner affinity and causes the same disease. The only property the alleles share is reduced thermostability, which points at the amount of functional clamp rather than at any lost interaction. But the inference is not closed: no experiment has shown that lowering PCNA levels by an unrelated means reproduces the cellular phenotype, and the S228I cells were explicitly reported to have normal PCNA protein levels, so a shared level-based mechanism has to explain how that allele produces the disease without a measured level change. Resolving this determines whether evidence gathered on one allele can be read as evidence about the disease, which is currently assumed throughout the literature and throughout this entry.
Show evidence (2 references)
PMID:36990216 SUPPORT DIRECT In Vitro
"Unlike PCNA-S228I, PCNA-C148S has WT-like structure and affinity toward partners."
The dissociation between the two alleles that this gap is about.
PMID:24911150 REFUTE DIRECT In Vitro
"Interestingly, while the p.Ser228Ile alteration appeared to have no effect on protein levels or DNA replication, patient cells exhibited marked abnormalities in response to UV irradiation, displaying substantial reductions in both UV survival and RNA synthesis recovery."
Recorded as REFUTE against the unified clamp-level account. If S228I cells have normal PCNA protein levels, then reduced clamp availability cannot be the whole mechanism for that allele, whatever the thermostability assays show in vitro.
Why does a repair defect that produces only subtle changes in undamaged cells produce progressive neurodegeneration in the whole organism?
KNOWLEDGE GAP cellular_defect_to_clinical_severity
Attached to
pathophysiology#Defective DNA Damage Response phenotypes#Neurodegeneration
The in vitro effects of the S228I allele on client binding are dramatic, and yet the downstream cellular consequences are described as subtle: p21 and Cdt1 stability are only minimally altered in patient cells, and DNA replication is unaffected. The authors of that work explicitly frame the gap - large biochemical perturbation, small cellular effect - and propose that the small effects accumulate. Nothing has tested that in neural tissue, and no model system for this disorder has been reported at all, so the step from a mild fibroblast phenotype to cerebellar atrophy is currently an argument rather than a finding.
Show evidence (1 reference)
PMID:28073635 SUPPORT DIRECT In Vitro
"Despite the dramatic in vitro effects of the PARD mutation on PIP-degron binding, there are only minor alterations to the stability of p21 and Cdt1 in cells from affected individuals."
States the disproportion between the biochemical and the cellular effect, which is what this gap is about. The paper's own title makes the same point.
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Pathophysiology

4
Biallelic Hypomorphic PCNA Variant
A homozygous missense substitution in PCNA that reduces but does not abolish function. The hypomorphic requirement is structural to the disease rather than incidental: PCNA is essential, so the alleles that can produce a living affected person are only those that leave enough function to support replication.
Disease follows from a reduced pool of functional PCNA Disease follows from specific lost PCNA client interactions
Genetic context PCNA hgnc:8729 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns PCNA (hgnc:8729). hgnc:8729 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
Two alleles are described: p.Ser228Ile, a founder allele in an Ohio Amish pedigree, and p.Cys148Ser. Both are homozygous in affected individuals. They differ in molecular consequence, which is why this entry carries two mechanistic hypotheses rather than one chain.
PCNA complex GO:0043626 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves PCNA complex (GO:0043626). GO:0043626 is a cellular component from the Gene Ontology.
Downstream
Impaired PCNA Client Protein Binding For the S228I allele, the substitution reshapes the interdomain connecting loop and the binding pocket that PIP-box clients dock into. Disease follows from specific lost PCNA client interactions
Reduced PCNA Thermostability Both described alleles destabilise the trimer, which is the one molecular property they have in common. Disease follows from a reduced pool of functional PCNA
Show evidence (3 references)
PMID:24911150 SUPPORT DIRECT Human Clinical
"Here, we describe a syndrome in which the cardinal clinical features include short stature, hearing loss, premature aging, telangiectasia, neurodegeneration, and photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence alteration of the proliferating cell nuclear antigen (PCNA)."
Establishes the gene, the allele and the phenotype in one statement.
PMID:24911150 SUPPORT DIRECT Other
"Due to this fundamental role, mutations in PCNA that profoundly impair protein function would be incompatible with life."
States the constraint that makes the hypomorphic requirement part of the disease definition. Graded OTHER: it is an argument from PCNA's known essentiality rather than a result reported in this paper.
PMID:36990216 SUPPORT DIRECT Human Clinical
"Here, we report a second PCNA substitution (C148S) that also causes PARD."
Establishes the second causal allele.
Impaired PCNA Client Protein Binding
PIP-box client proteins bind the altered PCNA pocket less well. The impairment is broad rather than selective, and includes Cdt1 and DNMT1 as well as the Okazaki-fragment enzymes. It is notably not universal: p21 still binds, which is what makes the defect a change in the pocket's preferences rather than its abolition.
Disease follows from specific lost PCNA client interactions
PCNA client protein binding Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased PCNA client protein binding. ↓ DECREASED
Downstream
Defective DNA Damage Response Losing the docking of repair and Okazaki-maturation enzymes onto the clamp is the route from the binding defect to a failure of repair. Disease follows from specific lost PCNA client interactions
Show evidence (7 references)
PMID:28073635 SUPPORT DIRECT In Vitro
"Analysis of the binding between PCNA and PCNA-interacting proteins (PIPs) shows that the S228I change dramatically impairs the majority of these interactions"
Quantifies the breadth of the interaction defect. Applies to the S228I allele only; the C148S allele does not share it.
PMID:28073635 SUPPORT DIRECT In Vitro
"In contrast p21 largely retains the ability to bind PCNA."
The exception that defines the shape of the defect, and the reason this node says "impaired" rather than "abolished".
PMID:26688547 SUPPORT DIRECT In Vitro
"Here, we describe the structure of the disease-causing variant, which reveals a large conformational change that dramatically transforms the binding pocket for PCNA client proteins."
The structural basis of this node. A crystal structure of S228I PCNA showing that the pocket itself is remodelled, which is what makes the interaction defect a property of the clamp rather than of any one partner.
+ 4 more references
Reduced PCNA Thermostability
The mutant trimer is less thermostable than wild type. In cells this presents as less PCNA loaded on chromatin and as phenotypes that vary with temperature, which is an unusual and clean signature: a disease whose cellular readout moves when you change the incubator.
Disease follows from a reduced pool of functional PCNA
regulation of protein stability GO:0031647 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulation of protein stability (GO:0031647). GO:0031647 is a biological process from the Gene Ontology. ↓ DECREASED
PCNA protein stability Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased PCNA protein stability. ↓ DECREASED
Downstream
Defective DNA Damage Response Less functional clamp on chromatin means fewer sites at which repair enzymes can be positioned, independently of any change in binding affinity. Disease follows from a reduced pool of functional PCNA
Show evidence (2 references)
PMID:36990216 SUPPORT DIRECT In Vitro
"Furthermore, patient-derived cells homozygous for the C148S allele exhibit low levels of chromatin-bound PCNA and display temperature-dependent phenotypes."
Connects the biophysical stability defect to a measurable cellular consequence in patient-derived material.
PMID:37511614 SUPPORT DIRECT In Vitro
"The impaired stability and increased aggregation behavior of PCNAC148S was confirmed by intrinsic tryptophan fluorescence, differential scanning fluorimetry (DSF) and asymmetrical flow field-flow fractionation (AF4) measurements."
Independent confirmation of the stability defect by a second group using three orthogonal biophysical methods, and it adds a mechanism the founding report did not name: increased aggregation. That matters for how this node should be read - a clamp that aggregates is removed from the functional pool as surely as one that unfolds, and it suggests why the cellular readout is temperature-dependent.
Defective DNA Damage Response
Patient cells survive UV irradiation poorly and fail to recover RNA synthesis after it. The RNA-synthesis-recovery deficit is the signature of impaired transcription-coupled nucleotide excision repair, and it is what puts this disorder among the NER-related diseases despite its ataxia-telangiectasia name. Basal DNA replication is unaffected, so this is a damage-response defect specifically rather than a general replication defect.
fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
nucleotide-excision repair GO:0006289 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased nucleotide-excision repair (GO:0006289). GO:0006289 is a biological process from the Gene Ontology. ↓ DECREASED transcription-coupled nucleotide-excision repair GO:0006283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased transcription-coupled nucleotide-excision repair (GO:0006283). GO:0006283 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Cutaneous Photosensitivity Failure to repair UV photoproducts in skin is the most direct clinical readout of the repair defect, and it is what aligns this disorder with the NER diseases.
Neurodegeneration Post-mitotic neurons depend on repair rather than on replacement, which is the standard account of why repair-deficiency syndromes are neurodegenerative. It is an account rather than a demonstration in this disease - no neuronal material has been studied - and the entry marks it accordingly.
Show evidence (2 references)
PMID:24911150 SUPPORT DIRECT In Vitro
"Interestingly, while the p.Ser228Ile alteration appeared to have no effect on protein levels or DNA replication, patient cells exhibited marked abnormalities in response to UV irradiation, displaying substantial reductions in both UV survival and RNA synthesis recovery."
The central cellular phenotype, and the dissociation from basal replication that makes this a damage-response defect. Note that the "no effect on protein levels" clause is specific to S228I and is contradicted for C148S by PMID:36990216 - the two alleles genuinely differ here.
PMID:28073635 SUPPORT DIRECT In Vitro
"Cells from individuals affected by PARD are sensitive to the PCNA inhibitors T3 and T2AA, showing that the S228I mutation has consequences for undamaged cells."
Extends the cellular defect beyond the irradiated state: the cells have reduced functional reserve even without exogenous damage.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Ataxia-Telangiectasia-Like Disorder 2 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

17
Cardiovascular 2
Telangiectasia HP:0001009 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Telangiectasia (HP:0001009). HP:0001009 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT Human Clinical
"All had several cutaneous telangiectasias, and 3 of 4 had conjunctival telangiectasia."
Gives both findings with their counts, which is the closest this literature comes to a frequency.
Conjunctival Telangiectasia HP:0000524 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Conjunctival telangiectasia (HP:0000524). HP:0000524 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT Human Clinical
"All had several cutaneous telangiectasias, and 3 of 4 had conjunctival telangiectasia."
Same sentence; the conjunctival finding with its 3-of-4 denominator.
Digestive 1
Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT Human Clinical
"Neurodegeneration was a consistent feature, characterized by progressive gait instability, muscle weakness, foot deformity, difficulties with speech and swallowing, learning difficulties, and cognitive decline with advancing age."
The swallowing half of the source's "difficulties with speech and swallowing". The source does not characterise the mechanism, so no bulbar or oesophageal claim is made.
Ear 2
Sensorineural Hearing Impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24911150 SUPPORT INDIRECT Human Clinical
"Here, we describe a syndrome in which the cardinal clinical features include short stature, hearing loss, premature aging, telangiectasia, neurodegeneration, and photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence alteration of the proliferating cell nuclear antigen (PCNA)."
Lists hearing loss as cardinal. Marked INDIRECT for the binding rather than the finding: the quote says "hearing loss" without specifying sensorineural, and the more specific HP term is bound on the basis of the fuller clinical description in the same paper rather than on this sentence.
Labyrinthine Dysplasia Abnormal inner ear morphology HP:0011390 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal inner ear morphology (HP:0011390). HP:0011390 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT Human Clinical
"Inner ear abnormalities included bilateral mild labyrinthine dysplasia with mildly dilated vestibules."
The imaging finding, with the source's own "mild" qualifier carried into severity.
Eye 1
Photophobia HP:0000613 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Photophobia (HP:0000613). HP:0000613 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT Human Clinical
"The principal features included neurodegeneration, postnatal growth retardation, prelingual sensorineural hearing loss, premature aging, ocular and cutaneous telangiectasia, learning difficulties, photophobia, and photosensitivity with evidence of predisposition to sun-induced malignancy."
Names photophobia among the principal features, separately from photosensitivity.
Integument 3
Cutaneous Photosensitivity HP:0000992 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cutaneous photosensitivity (HP:0000992). HP:0000992 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36990216 SUPPORT DIRECT Human Clinical
"PARD symptoms range from UV sensitivity, neurodegeneration, telangiectasia, and premature aging."
Lists UV sensitivity among the clinical features.
Premature Aging Prematurely aged appearance HP:0007495 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prematurely aged appearance (HP:0007495). HP:0007495 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT Human Clinical
"The principal features included neurodegeneration, postnatal growth retardation, prelingual sensorineural hearing loss, premature aging, ocular and cutaneous telangiectasia, learning difficulties, photophobia, and photosensitivity with evidence of predisposition to sun-induced malignancy."
Names premature aging among the principal features in all four affected members of the founding pedigree. Note the whole clinical description of this disorder rests on that one kindred.
Predisposition to Sun-Induced Skin Malignancy Neoplasm of the skin HP:0008069 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neoplasm of the skin (HP:0008069). HP:0008069 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT Human Clinical
"The principal features included neurodegeneration, postnatal growth retardation, prelingual sensorineural hearing loss, premature aging, ocular and cutaneous telangiectasia, learning difficulties, photophobia, and photosensitivity with evidence of predisposition to sun-induced malignancy."
States the predisposition with the authors' own "evidence of" qualifier, which is why this row asserts a predisposition rather than a malignancy frequency.
Limbs 1
Foot Deformity Abnormal foot morphology HP:0001760 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal foot morphology (HP:0001760). HP:0001760 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT Human Clinical
"Neurodegeneration was a consistent feature, characterized by progressive gait instability, muscle weakness, foot deformity, difficulties with speech and swallowing, learning difficulties, and cognitive decline with advancing age."
Names the finding. It is listed among the neurodegenerative features, so a neurogenic rather than primary skeletal origin is implied but not stated.
Musculoskeletal 1
Muscle Weakness HP:0001324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle weakness (HP:0001324). HP:0001324 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT Human Clinical
"Neurodegeneration was a consistent feature, characterized by progressive gait instability, muscle weakness, foot deformity, difficulties with speech and swallowing, learning difficulties, and cognitive decline with advancing age."
Names muscle weakness among the neurodegenerative features.
Nervous System 5
Neurodegeneration HP:0002180 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurodegeneration (HP:0002180). HP:0002180 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT Human Clinical
"Here, we describe a syndrome in which the cardinal clinical features include short stature, hearing loss, premature aging, telangiectasia, neurodegeneration, and photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence alteration of the proliferating cell nuclear antigen (PCNA)."
Lists neurodegeneration among the cardinal features.
Cerebellar Atrophy HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272). HP:0001272 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT Human Clinical
"Neuroimaging was only available in 1 case (patient VI:7): MRI of the brain at 8 years of age demonstrated cerebellar atrophy involving the cerebellar vermis and hemispheres."
Reports the finding and, in the same sentence, its denominator. The quote is chosen deliberately over a summary statement because "only available in 1 case" is information a reader needs in order to weigh the finding.
Cognitive Decline Cognitive impairment HP:0100543 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cognitive impairment (HP:0100543), qualified as course progressive. HP:0100543 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT Human Clinical
"Neurodegeneration was a consistent feature, characterized by progressive gait instability, muscle weakness, foot deformity, difficulties with speech and swallowing, learning difficulties, and cognitive decline with advancing age."
States both the childhood learning difficulty and the later decline, which is why the phenotype term carries clinical_course PROGRESSIVE.
Progressive Gait Instability Gait ataxia HP:0002066 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gait ataxia (HP:0002066), qualified as course progressive. HP:0002066 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT Human Clinical
"Neurodegeneration was a consistent feature, characterized by progressive gait instability, muscle weakness, foot deformity, difficulties with speech and swallowing, learning difficulties, and cognitive decline with advancing age."
Names the gait instability and its progressive character. Bound to gait ataxia because the disorder's cerebellar atrophy is curated here and the clinical label is ataxia, though the source says only "gait instability".
Dysarthria HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24911150 SUPPORT INDIRECT Human Clinical
"Neurodegeneration was a consistent feature, characterized by progressive gait instability, muscle weakness, foot deformity, difficulties with speech and swallowing, learning difficulties, and cognitive decline with advancing age."
INDIRECT because the source says "difficulties with speech" without specifying dysarthria; the binding narrows to the motor-speech reading that the surrounding neurodegenerative and bulbar features support, and no aphasia claim is made.
Growth 1
Short Stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT Human Clinical
"Here, we describe a syndrome in which the cardinal clinical features include short stature, hearing loss, premature aging, telangiectasia, neurodegeneration, and photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence alteration of the proliferating cell nuclear antigen (PCNA)."
Lists short stature as cardinal.
🧬

Genetic Associations

1
PCNA
Gene: PCNA hgnc:8729 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PCNA (hgnc:8729). hgnc:8729 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT Human Clinical
"PCNA is a highly conserved sliding clamp protein essential for DNA replication and repair."
States the gene product's function and its essentiality.
🌍

Environmental Factors

1
Ultraviolet radiation exposure
exposure to ultraviolet radiation ECTO:0000006 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to ultraviolet radiation (ECTO:0000006). ECTO:0000006 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Solar UV, the one environmental factor with a demonstrated interaction with this disorder's molecular defect. The pathophysiology here is not caused by exposure - the disease is the repair defect - but UV is what converts that defect into a visible cellular and cutaneous phenotype, which is why the link is EXACERBATES rather than TRIGGERS. Note the interaction is demonstrated in patient fibroblasts under controlled irradiation; no source cited here reports a dose-response in patients, so this is the mechanism of the exposure rather than a quantified clinical risk.
Show evidence (1 reference)
PMID:24911150 SUPPORT INDIRECT Human Clinical
"The principal features included neurodegeneration, postnatal growth retardation, prelingual sensorineural hearing loss, premature aging, ocular and cutaneous telangiectasia, learning difficulties, photophobia, and photosensitivity with evidence of predisposition to sun-induced malignancy."
The clinical counterpart of the cellular result: photosensitivity and sun-induced malignancy are the patient-level consequences of UV exposure meeting this repair defect. INDIRECT because the sentence reports the phenotypes rather than the exposure relationship.
Mechanism Target:
EXACERBATES Defective DNA Damage Response — UV generates the helix-distorting lesions that nucleotide excision repair exists to remove, so it is the challenge under which the repair deficit becomes measurable. Patient cells are near-normal until irradiated.
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT In Vitro
"Ser228Ile alteration appeared to have no effect on protein levels or DNA replication, patient cells exhibited marked abnormalities in response to UV irradiation, displaying substantial reductions in both UV survival and RNA synthesis recovery."
The clearest statement of the interaction: unremarkable at baseline, deficient under UV. It is also the sentence that keeps this an exacerbating rather than an initiating exposure, since the defect exists without it.
🔬

Diagnosis

2
PCNA Sequencing
Molecular confirmation is by sequencing PCNA. In practice the disorder is reached from a clinical suspicion of a DNA repair syndrome, since the phenotype overlaps several of them and none of the individual features is specific.
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT Human Clinical
"Here, we describe a syndrome in which the cardinal clinical features include short stature, hearing loss, premature aging, telangiectasia, neurodegeneration, and photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence alteration of the proliferating cell nuclear antigen (PCNA)."
Establishes the gene that confirmatory sequencing targets.
UV Sensitivity and RNA Synthesis Recovery in Patient Fibroblasts
The cellular assays that characterise the disorder: reduced survival after UV and failure to recover RNA synthesis afterwards. These are research assays rather than routine diagnostics, but they are what places the disorder among the nucleotide excision repair diseases and would distinguish it from a purely clinical ataxia-telangiectasia-like picture.
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT In Vitro
"Interestingly, while the p.Ser228Ile alteration appeared to have no effect on protein levels or DNA replication, patient cells exhibited marked abnormalities in response to UV irradiation, displaying substantial reductions in both UV survival and RNA synthesis recovery."
Names both assays and their direction in patient cells.
📊

Prevalence

1
Ohio Amish community
Cases In Literature Ultra Rare
The founding report describes four affected individuals in one extended pedigree. No population rate is available, and the founder structure means a rate estimated here would not transfer to any other population.
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT Human Clinical
"In the current study, 4 individuals aged 11-31 years affected by a novel syndrome were identified from a single extended pedigree consisting of 2 kindreds within the Ohio Amish community"
Gives the entire molecularly characterised population of the original report, and its founder structure.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Ataxia-Telangiectasia-Like Disorder 2:

Ataxia-telangiectasia (ATM)
Overlapping Features The disorder this one is named after. Both present with ataxia and telangiectasia, but ATM disease is a double-strand-break signalling defect with immunodeficiency, raised alpha-fetoprotein and a substantial malignancy risk, none of which characterises this entry. Photosensitivity is not a feature of ataxia-telangiectasia and is a feature here.
Distinguishing Features
  • Cutaneous photosensitivity and impaired RNA synthesis recovery after UV, absent in ATM disease
  • No immunodeficiency or raised alpha-fetoprotein reported in the PCNA disorder
  • Short stature, hearing loss and premature aging are cardinal here
  • Oculomotor apraxia, common in ataxia telangiectasia, is absent in the reported PCNA patients
Show evidence (3 references)
PMID:33426167 SUPPORT DIRECT Human Clinical
"However, absence of telangiectasia, normal levels of alpha-fetoprotein and negative genetic test may direct to alternative diagnosis with similar phenotypes such as ataxia telangiectasia-like disorders (ATLD)."
States the clinical route by which a patient reaches this differential at all, which is the practical content of this row: the ATLD label is what is left when ataxia telangiectasia has been looked for and not found.
PMID:24911150 SUPPORT DIRECT Human Clinical
"Ser228Ile and AT, including an absence of both the immunodeficiency and oculomotor apraxia commonly seen in AT-affected individuals."
The evidence for the distinguishing feature above, from the founding report rather than from the ATLD nosology review. It also supplies a second discriminator the row did not name: oculomotor apraxia, absent here and common in ataxia telangiectasia.
PMID:24911150 SUPPORT INDIRECT Human Clinical
"normal chromosomes (untreated or gamma ray-induced; patient VI:11), alpha-fetoprotein (AFP) levels, Ig patterns"
Records that AFP and immunoglobulins were measured and normal, which is what makes the absence a finding rather than an untested assumption. INDIRECT: it is a methods-level list of what was normal, in one patient, not a statement about the disorder.
Ataxia-telangiectasia-like disorder 1 (MRE11)
Overlapping Features Shares the clinical label and the numbering but not the mechanism: ATLD1 is caused by MRE11 variants and is a double-strand-break repair defect. The shared name reflects the era in which both were described clinically, and grouping the two by mechanism would be a mistake.
Distinguishing Features
  • Caused by MRE11 rather than PCNA
  • Double-strand-break repair rather than nucleotide excision repair
  • No UV photosensitivity phenotype
  • Loss of MRE11 protein on western blot, with reduced ATM-dependent phosphorylation
  • Reported additional features not described in ATLD2, including hypergonadotropic hypogonadism and neutrophil hypersegmentation
Show evidence (3 references)
PMID:24733832 SUPPORT DIRECT Human Clinical
"Western blot assay demonstrated total loss of MRE11 and reduction of ATM-dependent phosphorylation; thus, we diagnosed ATLD."
The laboratory signature that separates ATLD1 from this entry at the bench. Note this reference and the one below describe ATLD1 patients, not ATLD2 ones, and are cited here only for the differential - the two disorders share a name and nothing else mechanistically, so quoting them anywhere else in this entry would be an error.
PMID:24733832 SUPPORT DIRECT Human Clinical
"We report a female ATLD patient presenting with hypergonadotropic hypogonadism and hypersegmented neutrophils, previously undescribed features in this disorder, and potential diagnostic clues to differentiate ATLD from other conditions."
Proposed ATLD1 discriminators. Recorded because they are features to look for when the differential is open, not because they have been sought and excluded in ATLD2; one patient, and the authors offer them as clues rather than criteria.
PMID:23436002 SUPPORT DIRECT Human Clinical
"Although the disease had early onset and the clinical picture was initially severe, suggesting ataxia-telangiectasia, neurological impairment, ocular motor apraxia and neuropsychological tests showed very slow deterioration in adult age."
Thirty years of follow-up in ATLD1, and the closest thing either disorder has to a natural history. Included so the differential carries a sense of course as well as of mechanism; no comparable long-term series exists for ATLD2.
Cockayne syndrome and other nucleotide excision repair disorders
Overlapping Features Mechanistically the closer relatives. Cockayne syndrome, UV-sensitive syndrome, xeroderma pigmentosum and trichothiodystrophy share the photosensitivity and the RNA-synthesis-recovery defect, and the founding report frames this disorder against exactly that set. Distinguishing them is a molecular rather than a clinical exercise.
Distinguishing Features
  • Caused by PCNA rather than by a core NER gene
  • Telangiectasia is prominent, which is not typical of the classical NER syndromes
Show evidence (1 reference)
PMID:24911150 SUPPORT DIRECT Other
"Numerous human disorders, including Cockayne syndrome, UV-sensitive syndrome, xeroderma pigmentosum, and trichothiodystrophy, result from the mutation of genes encoding molecules important for nucleotide excision repair."
Names the disorder class this entry is framed against, in the founding report's own opening sentence.
{ }

Source YAML

click to show 
name: Ataxia-Telangiectasia-Like Disorder 2
creation_date: "2026-09-10T00:00:00Z"
category: Mendelian
description: >-
  Ataxia-telangiectasia-like disorder 2, better known in the molecular literature as
  PCNA-associated DNA repair disorder (PARD), is an autosomal recessive syndrome of short
  stature, sensorineural hearing loss, premature aging, cutaneous and conjunctival
  telangiectasia, progressive neurodegeneration with cerebellar atrophy, and cutaneous
  photosensitivity. It is caused by biallelic hypomorphic variants in PCNA, the sliding
  clamp that tethers the enzymes of DNA replication and repair to the template.

  The disorder exists only because the alleles are hypomorphic, and this is not a
  throwaway observation about severity. PCNA is essential; an allele that abolished its
  function would not be compatible with life, so the mutational window that can produce a
  viable human phenotype is narrow. Everything about the entry follows from that
  constraint - the founder origin of the first-described allele in an Amish pedigree, the
  small number of families, and the fact that basal DNA replication is essentially intact
  while the damage response is not.

  Two causal alleles are now described and they do not share a molecular mechanism. The
  original p.Ser228Ile substitution reshapes PCNA's partner-binding pocket and impairs
  interaction with a long list of client proteins, including flap endonuclease 1 and DNA
  ligase 1. The later p.Cys148Ser substitution leaves the structure and partner affinity
  looking like wild type. What the two share is a thermostability defect, and cells
  carrying the C148S allele have less PCNA on chromatin and show temperature-dependent
  phenotypes - which points at the amount of functional clamp available, rather than any
  one lost interaction, as the variable the disease actually tracks. That convergence is
  the most interesting thing in the entry and is curated as an explicit alternative
  mechanistic hypothesis rather than folded into a single chain.

  The name is a clinical description that has aged badly. The phenotype resembles
  ataxia-telangiectasia enough to have been labelled after it, but the mechanism is
  nucleotide-excision-repair-like photosensitivity rather than the double-strand-break
  signalling defect of ATM or MRE11 disease, and the "2" positions it as a sibling of
  MRE11-related ATLD1 which it does not mechanistically resemble.
synonyms:
- ATLD2
- PARD
- PCNA-associated DNA repair disorder
- PCNA-related DNA repair disorder
disease_term:
  preferred_term: ataxia-telangiectasia-like disorder 2
  term:
    id: MONDO:0014399
    label: ataxia-telangiectasia-like disorder 2
parents:
- DNA Repair Disorder
- Progeroid Syndrome
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      An autosomal recessive Mendelian DNA repair disorder identified through
      homozygosity mapping in a founder population.
  - classification_value: NEUROLOGIC
    notes: >-
      The dominant progressive burden is neurological: cerebellar atrophy and
      neurodegeneration, which is what brings affected individuals to attention over time.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0014399
      label: ataxia-telangiectasia-like disorder 2
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The dismech entry and the MONDO class denote the same entity: the PCNA-related
      recessive DNA repair disorder. The molecular literature calls it PARD, which is
      recorded as a synonym rather than as a separate concept.
references:
- reference: PMID:24911150
  title: "Hypomorphic PCNA mutation underlies a human DNA repair disorder."
- reference: PMID:28073635
  title: "PCNA dependent cellular activities tolerate dramatic perturbations in PCNA client interactions."
- reference: PMID:36990216
  title: "A thermosensitive PCNA allele underlies an ataxia-telangiectasia-like disorder."
- reference: PMID:17236820
  title: Neurons and astrocytes exhibit lower activities of global genome nucleotide excision repair than do fibroblasts.
- reference: PMID:17994007
  title: The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA.
- reference: PMID:23535145
  title: Dissection of cell cycle-dependent dynamics of Dnmt1 by FRAP and diffusion-coupled modeling.
- reference: PMID:25972089
  title: p21 Exploits Residue Tyr151 as a Tether for High-Affinity PCNA Binding.
- reference: PMID:26688547
  title: A Disease-Causing Variant in PCNA Disrupts a Promiscuous Protein Binding Site.
- reference: PMID:33426167
  title: "Beyond Typical Ataxia Telangiectasia: How to Identify the Ataxia Telangiectasia-Like Disorders."
- reference: PMID:33984330
  title: "Unlocking the PIP-box: A peptide library reveals interactions that drive high-affinity binding to human PCNA."
- reference: PMID:37511614
  title: A FRET-Based Assay for the Identification of PCNA Inhibitors.
- reference: PMID:23436002
  title: Clinical course of two Italian siblings with ataxia-telangiectasia-like disorder.
- reference: PMID:24733832
  title: "Hypergonadotropic hypogonadism and hypersegmented neutrophils in a patient with ataxia-telangiectasia-like disorder: potential diagnostic clues?"
prevalence:
- population: Ohio Amish community
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The founding report describes four affected individuals in one extended pedigree. No
    population rate is available, and the founder structure means a rate estimated here
    would not transfer to any other population.
  evidence:
  - reference: PMID:24911150
    reference_title: "Hypomorphic PCNA mutation underlies a human DNA repair disorder."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the current study, 4 individuals aged 11-31 years affected by a novel syndrome
      were identified from a single extended pedigree consisting of 2 kindreds within the
      Ohio Amish community
    explanation: >-
      Gives the entire molecularly characterised population of the original report, and
      its founder structure.
mechanistic_hypotheses:
- hypothesis_group_id: lost_client_interactions
  hypothesis_label: Disease follows from specific lost PCNA client interactions
  status: CANONICAL
  description: >-
    The account that came with the founding report. The p.Ser228Ile substitution alters
    the partner-binding pocket, PCNA's interactions with flap endonuclease 1, DNA ligase 1
    and a long list of other PIP-box clients are impaired, and the resulting failures of
    repair and of Okazaki-fragment maturation produce the phenotype. It explains the
    photosensitivity and the UV phenotypes of patient cells directly.
  evidence:
  - reference: PMID:24911150
    reference_title: "Hypomorphic PCNA mutation underlies a human DNA repair disorder."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "The p.Ser228Ile change also profoundly altered PCNA's interaction with Flap endonuclease 1 and DNA Ligase 1, DNA metabolism enzymes."
    explanation: Reports the interaction defect this hypothesis is built on.
- hypothesis_group_id: reduced_functional_clamp_pool
  hypothesis_label: Disease follows from a reduced pool of functional PCNA
  status: EMERGING
  description: >-
    The account that the second allele forces. p.Cys148Ser causes the same disease with
    wild-type-like structure and wild-type-like partner affinity, so lost client binding
    cannot be the common cause. What both alleles do share is reduced thermostability, and
    C148S patient cells carry less PCNA on chromatin and behave differently at different
    temperatures. On this reading the operative variable is how much functional clamp is
    available, and the S228I interaction defects are one route to that rather than the
    mechanism itself.
  evidence:
  - reference: PMID:36990216
    reference_title: "A thermosensitive PCNA allele underlies an ataxia-telangiectasia-like disorder."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "The stability defect of both PARD variants indicates that PCNA levels are likely an important driver of PARD disease."
    explanation: >-
      States the hypothesis in the authors' own terms, and note their own hedge - "likely
      an important driver", not "the cause" - which is why this is EMERGING and not
      CANONICAL.
  - reference: PMID:36990216
    reference_title: "A thermosensitive PCNA allele underlies an ataxia-telangiectasia-like disorder."
    supports: REFUTE
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "Unlike PCNA-S228I, PCNA-C148S has WT-like structure and affinity toward partners."
    explanation: >-
      Recorded as REFUTE against the lost-client-interaction hypothesis as a complete
      account. A second allele causing the same disease without the interaction defect is
      the observation that makes the canonical mechanism insufficient.
  - reference: PMID:37511614
    reference_title: "A FRET-Based Assay for the Identification of PCNA Inhibitors."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Incubation time dependent FRET measurements indicated no effect on PCNAC148S-p15
      affinity, but on PCNA stability.
    explanation: >-
      An independent replication of the C148S result by a different group using different
      methods (FRET, intrinsic tryptophan fluorescence, differential scanning fluorimetry
      and asymmetrical flow field-flow fractionation), and the reason this hypothesis rests
      on more than one laboratory's assay. It separates the two axes cleanly: partner
      affinity intact, stability not.
pathophysiology:
- name: Biallelic Hypomorphic PCNA Variant
  biological_scale: MOLECULAR
  description: >-
    A homozygous missense substitution in PCNA that reduces but does not abolish function.
    The hypomorphic requirement is structural to the disease rather than incidental: PCNA
    is essential, so the alleles that can produce a living affected person are only those
    that leave enough function to support replication.
  genetic_context:
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    gene:
      preferred_term: PCNA
      term:
        id: hgnc:8729
        label: PCNA
    description: >-
      Two alleles are described: p.Ser228Ile, a founder allele in an Ohio Amish pedigree,
      and p.Cys148Ser. Both are homozygous in affected individuals. They differ in
      molecular consequence, which is why this entry carries two mechanistic hypotheses
      rather than one chain.
  cellular_components:
  - preferred_term: PCNA complex
    term:
      id: GO:0043626
      label: PCNA complex
  evidence:
  - reference: PMID:24911150
    reference_title: "Hypomorphic PCNA mutation underlies a human DNA repair disorder."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a syndrome in which the cardinal clinical features include short
      stature, hearing loss, premature aging, telangiectasia, neurodegeneration, and
      photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence
      alteration of the proliferating cell nuclear antigen (PCNA).
    explanation: Establishes the gene, the allele and the phenotype in one statement.
  - reference: PMID:24911150
    reference_title: "Hypomorphic PCNA mutation underlies a human DNA repair disorder."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    snippet: "Due to this fundamental role, mutations in PCNA that profoundly impair protein function would be incompatible with life."
    explanation: >-
      States the constraint that makes the hypomorphic requirement part of the disease
      definition. Graded OTHER: it is an argument from PCNA's known essentiality rather
      than a result reported in this paper.
  - reference: PMID:36990216
    reference_title: "A thermosensitive PCNA allele underlies an ataxia-telangiectasia-like disorder."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a second PCNA substitution (C148S) that also causes PARD."
    explanation: Establishes the second causal allele.
  downstream:
  - target: Impaired PCNA Client Protein Binding
    description: >-
      For the S228I allele, the substitution reshapes the interdomain connecting loop and
      the binding pocket that PIP-box clients dock into.
    causal_link_type: DIRECT
    hypothesis_groups:
    - lost_client_interactions
    evidence:
    - reference: PMID:28073635
      reference_title: "PCNA dependent cellular activities tolerate dramatic perturbations in PCNA client interactions."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: "Ubiquitination of PCNA is unaffected by the S228I change, which indirectly alters the structure of the inter-domain connecting loop."
      explanation: >-
        Localises the structural consequence of the allele, and simultaneously records
        what it does not disturb.
  - target: Reduced PCNA Thermostability
    description: >-
      Both described alleles destabilise the trimer, which is the one molecular property
      they have in common.
    causal_link_type: DIRECT
    hypothesis_groups:
    - reduced_functional_clamp_pool
    evidence:
    - reference: PMID:36990216
      reference_title: "A thermosensitive PCNA allele underlies an ataxia-telangiectasia-like disorder."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: "In contrast, both disease-associated variants possess a thermostability defect."
      explanation: >-
        The shared property across the two alleles, measured directly on the purified
        proteins.
- name: Impaired PCNA Client Protein Binding
  biological_scale: MOLECULAR
  description: >-
    PIP-box client proteins bind the altered PCNA pocket less well. The impairment is
    broad rather than selective, and includes Cdt1 and DNMT1 as well as the
    Okazaki-fragment enzymes. It is notably not universal: p21 still binds, which is what
    makes the defect a change in the pocket's preferences rather than its abolition.
  molecular_functions:
  - preferred_term: PCNA client protein binding
    modifier: DECREASED
  evidence:
  - reference: PMID:28073635
    reference_title: "PCNA dependent cellular activities tolerate dramatic perturbations in PCNA client interactions."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Analysis of the binding between PCNA and PCNA-interacting proteins (PIPs) shows that
      the S228I change dramatically impairs the majority of these interactions
    explanation: >-
      Quantifies the breadth of the interaction defect. Applies to the S228I allele only;
      the C148S allele does not share it.
  - reference: PMID:28073635
    reference_title: "PCNA dependent cellular activities tolerate dramatic perturbations in PCNA client interactions."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "In contrast p21 largely retains the ability to bind PCNA."
    explanation: >-
      The exception that defines the shape of the defect, and the reason this node says
      "impaired" rather than "abolished".
  - reference: PMID:26688547
    reference_title: "A Disease-Causing Variant in PCNA Disrupts a Promiscuous Protein Binding Site."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we describe the structure of the disease-causing variant, which reveals a large
      conformational change that dramatically transforms the binding pocket for PCNA client
      proteins.
    explanation: >-
      The structural basis of this node. A crystal structure of S228I PCNA showing that the
      pocket itself is remodelled, which is what makes the interaction defect a property of
      the clamp rather than of any one partner.
  - reference: PMID:26688547
    reference_title: "A Disease-Causing Variant in PCNA Disrupts a Promiscuous Protein Binding Site."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      We show that the mutation markedly alters the binding energetics for some client
      proteins, while another, p21(CIP1), is only mildly affected.
    explanation: >-
      Independent structural confirmation of the p21 exception recorded above, from a
      different group and a different method. Two laboratories reaching the same asymmetry
      is why this node states the exception rather than hedging it.
  - reference: PMID:26688547
    reference_title: "A Disease-Causing Variant in PCNA Disrupts a Promiscuous Protein Binding Site."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Structures of the disease variant bound to peptides derived from two PCNA partner
      proteins reveal that the binding pocket can adjust conformation to accommodate some
      ligands, indicating that the binding site is dynamic and pliable.
    explanation: >-
      Explains why the defect is selective rather than uniform: the remodelled pocket can
      still flex to fit some ligands. Curated as its own item because it is the mechanism
      behind the exception, not a restatement of it.
  - reference: PMID:25972089
    reference_title: "p21 Exploits Residue Tyr151 as a Tether for High-Affinity PCNA Binding."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      As p21 is one of the few PIP-box sequences to contain a tyrosine rather than a
      phenylalanine in the eighth conserved position, we probed the significance of the
      hydroxyl group at this position using a mutational approach.
    explanation: >-
      A candidate explanation for why p21 in particular survives the pocket remodelling:
      it is an atypical PIP-box with the highest known affinity for PCNA, tethered by a
      residue most partners do not have. INDIRECT because this work is on wild-type PCNA
      and does not test the disease variant, so the connection to the exception is an
      inference.
  - reference: PMID:33984330
    reference_title: "Unlocking the PIP-box: A peptide library reveals interactions that drive high-affinity binding to human PCNA."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      The hPCNA-binding affinity of all peptides, characterized as KD values determined by
      surface plasmon resonance, spanned a 4000-fold range, from 1.83 nM to 7.59 μM.
    explanation: >-
      Sets the scale the selectivity of this defect has to be read against. Native PIP-box
      affinities already span four orders of magnitude, so a pocket change that shifts
      binding energetics will not affect all partners equally even before any structural
      accommodation. INDIRECT: it characterises wild-type PCNA, not the variant.
  downstream:
  - target: Defective DNA Damage Response
    description: >-
      Losing the docking of repair and Okazaki-maturation enzymes onto the clamp is the
      route from the binding defect to a failure of repair.
    causal_link_type: DIRECT
    hypothesis_groups:
    - lost_client_interactions
    evidence:
    - reference: PMID:24911150
      reference_title: "Hypomorphic PCNA mutation underlies a human DNA repair disorder."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "The p.Ser228Ile change also profoundly altered PCNA's interaction with Flap endonuclease 1 and DNA Ligase 1, DNA metabolism enzymes."
      explanation: >-
        Names two of the affected enzymes. Marked INDIRECT because the quote reports the
        interaction defect, and the step to a defective damage response is an inference
        from what those enzymes do.
- name: Reduced PCNA Thermostability
  biological_scale: MOLECULAR
  description: >-
    The mutant trimer is less thermostable than wild type. In cells this presents as less
    PCNA loaded on chromatin and as phenotypes that vary with temperature, which is an
    unusual and clean signature: a disease whose cellular readout moves when you change
    the incubator.
  molecular_functions:
  - preferred_term: PCNA protein stability
    modifier: DECREASED
  biological_processes:
  - preferred_term: regulation of protein stability
    modifier: DECREASED
    term:
      id: GO:0031647
      label: regulation of protein stability
  evidence:
  - reference: PMID:36990216
    reference_title: "A thermosensitive PCNA allele underlies an ataxia-telangiectasia-like disorder."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, patient-derived cells homozygous for the C148S allele exhibit low levels
      of chromatin-bound PCNA and display temperature-dependent phenotypes.
    explanation: >-
      Connects the biophysical stability defect to a measurable cellular consequence in
      patient-derived material.
  - reference: PMID:37511614
    reference_title: "A FRET-Based Assay for the Identification of PCNA Inhibitors."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      The impaired stability and increased aggregation behavior of PCNAC148S was confirmed
      by intrinsic tryptophan fluorescence, differential scanning fluorimetry (DSF) and
      asymmetrical flow field-flow fractionation (AF4) measurements.
    explanation: >-
      Independent confirmation of the stability defect by a second group using three
      orthogonal biophysical methods, and it adds a mechanism the founding report did not
      name: increased aggregation. That matters for how this node should be read - a clamp
      that aggregates is removed from the functional pool as surely as one that unfolds,
      and it suggests why the cellular readout is temperature-dependent.
  downstream:
  - target: Defective DNA Damage Response
    description: >-
      Less functional clamp on chromatin means fewer sites at which repair enzymes can be
      positioned, independently of any change in binding affinity.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - reduced_functional_clamp_pool
    evidence:
    - reference: PMID:36990216
      reference_title: "A thermosensitive PCNA allele underlies an ataxia-telangiectasia-like disorder."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "The stability defect of both PARD variants indicates that PCNA levels are likely an important driver of PARD disease."
      explanation: >-
        The authors' own inferential statement, quoted with its hedge intact. INDIRECT
        because it is an interpretation offered by the paper rather than a measured link
        from clamp level to repair failure.
- name: Defective DNA Damage Response
  biological_scale: CELLULAR
  description: >-
    Patient cells survive UV irradiation poorly and fail to recover RNA synthesis after
    it. The RNA-synthesis-recovery deficit is the signature of impaired
    transcription-coupled nucleotide excision repair, and it is what puts this disorder among the
    NER-related diseases despite its ataxia-telangiectasia name. Basal DNA replication is
    unaffected, so this is a damage-response defect specifically rather than a general
    replication defect.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: nucleotide-excision repair
    modifier: DECREASED
    term:
      id: GO:0006289
      label: nucleotide-excision repair
  - preferred_term: transcription-coupled nucleotide-excision repair
    modifier: DECREASED
    term:
      id: GO:0006283
      label: transcription-coupled nucleotide-excision repair
  evidence:
  - reference: PMID:24911150
    reference_title: "Hypomorphic PCNA mutation underlies a human DNA repair disorder."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Interestingly, while the p.Ser228Ile alteration appeared to have no effect on protein
      levels or DNA replication, patient cells exhibited marked abnormalities in response
      to UV irradiation, displaying substantial reductions in both UV survival and RNA
      synthesis recovery.
    explanation: >-
      The central cellular phenotype, and the dissociation from basal replication that
      makes this a damage-response defect. Note that the "no effect on protein levels"
      clause is specific to S228I and is contradicted for C148S by PMID:36990216 - the two
      alleles genuinely differ here.
  - reference: PMID:28073635
    reference_title: "PCNA dependent cellular activities tolerate dramatic perturbations in PCNA client interactions."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "Cells from individuals affected by PARD are sensitive to the PCNA inhibitors T3 and T2AA, showing that the S228I mutation has consequences for undamaged cells."
    explanation: >-
      Extends the cellular defect beyond the irradiated state: the cells have reduced
      functional reserve even without exogenous damage.
  downstream:
  - target: Cutaneous Photosensitivity
    description: >-
      Failure to repair UV photoproducts in skin is the most direct clinical readout of
      the repair defect, and it is what aligns this disorder with the NER diseases.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24911150
      reference_title: "Hypomorphic PCNA mutation underlies a human DNA repair disorder."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Together, our findings detail a mutation of PCNA in humans associated with a
        neurodegenerative phenotype, displaying clinical and molecular features common to
        other DNA repair disorders, which we showed to be attributable to a hypomorphic
        amino acid alteration.
      explanation: >-
        Places the clinical picture with the DNA repair disorders. INDIRECT: the quote
        asserts the class membership, and the step to "the UV repair defect causes this
        patient's photosensitivity" is the inference.
  - target: Neurodegeneration
    description: >-
      Post-mitotic neurons depend on repair rather than on replacement, which is the
      standard account of why repair-deficiency syndromes are neurodegenerative. It is
      an account rather than a demonstration in this disease - no neuronal material has
      been studied - and the entry marks it accordingly.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36990216
      reference_title: "A thermosensitive PCNA allele underlies an ataxia-telangiectasia-like disorder."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "PARD symptoms range from UV sensitivity, neurodegeneration, telangiectasia, and premature aging."
      explanation: >-
        Establishes that neurodegeneration is part of the syndrome. It does not establish
        the causal route from the repair defect to neuronal loss, which is why the edge is
        typed with unknown intermediates.
phenotypes:
- category: Neurologic
  name: Neurodegeneration
  description: Progressive neurological deterioration, one of the cardinal features.
  phenotype_term:
    preferred_term: Neurodegeneration
    term:
      id: HP:0002180
      label: Neurodegeneration
  evidence:
  - reference: PMID:24911150
    reference_title: "Hypomorphic PCNA mutation underlies a human DNA repair disorder."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a syndrome in which the cardinal clinical features include short
      stature, hearing loss, premature aging, telangiectasia, neurodegeneration, and
      photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence
      alteration of the proliferating cell nuclear antigen (PCNA).
    explanation: Lists neurodegeneration among the cardinal features.
- category: Neurologic
  name: Cerebellar Atrophy
  description: >-
    Cerebellar atrophy affecting vermis and hemispheres. Recorded with an explicit caveat:
    imaging was obtained in one of the four originally reported individuals, so this is a
    single observation rather than a series finding.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:24911150
    reference_title: "Hypomorphic PCNA mutation underlies a human DNA repair disorder."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neuroimaging was only available in 1 case (patient VI:7): MRI of the brain at 8 years
      of age demonstrated cerebellar atrophy involving the cerebellar vermis and
      hemispheres.
    explanation: >-
      Reports the finding and, in the same sentence, its denominator. The quote is chosen
      deliberately over a summary statement because "only available in 1 case" is
      information a reader needs in order to weigh the finding.
- category: Dermatologic
  name: Telangiectasia
  description: >-
    Cutaneous telangiectasia in all four originally reported individuals, and conjunctival
    telangiectasia in three of them. The feature is what earned the disorder its
    ataxia-telangiectasia-like name.
  phenotype_term:
    preferred_term: Telangiectasia
    term:
      id: HP:0001009
      label: Telangiectasia
  evidence:
  - reference: PMID:24911150
    reference_title: "Hypomorphic PCNA mutation underlies a human DNA repair disorder."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "All had several cutaneous telangiectasias, and 3 of 4 had conjunctival telangiectasia."
    explanation: >-
      Gives both findings with their counts, which is the closest this literature comes to
      a frequency.
- category: Ophthalmologic
  name: Conjunctival Telangiectasia
  description: Present in three of the four originally reported individuals.
  phenotype_term:
    preferred_term: Conjunctival telangiectasia
    term:
      id: HP:0000524
      label: Conjunctival telangiectasia
  evidence:
  - reference: PMID:24911150
    reference_title: "Hypomorphic PCNA mutation underlies a human DNA repair disorder."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "All had several cutaneous telangiectasias, and 3 of 4 had conjunctival telangiectasia."
    explanation: Same sentence; the conjunctival finding with its 3-of-4 denominator.
- category: Dermatologic
  name: Cutaneous Photosensitivity
  description: >-
    Abnormal skin reaction to sunlight, the clinical correlate of the nucleotide excision
    repair defect.
  phenotype_term:
    preferred_term: Cutaneous photosensitivity
    term:
      id: HP:0000992
      label: Cutaneous photosensitivity
  evidence:
  - reference: PMID:36990216
    reference_title: "A thermosensitive PCNA allele underlies an ataxia-telangiectasia-like disorder."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "PARD symptoms range from UV sensitivity, neurodegeneration, telangiectasia, and premature aging."
    explanation: Lists UV sensitivity among the clinical features.
- category: Auditory
  name: Sensorineural Hearing Impairment
  description: Hearing loss, one of the cardinal features of the syndrome.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:24911150
    reference_title: "Hypomorphic PCNA mutation underlies a human DNA repair disorder."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a syndrome in which the cardinal clinical features include short
      stature, hearing loss, premature aging, telangiectasia, neurodegeneration, and
      photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence
      alteration of the proliferating cell nuclear antigen (PCNA).
    explanation: >-
      Lists hearing loss as cardinal. Marked INDIRECT for the binding rather than the
      finding: the quote says "hearing loss" without specifying sensorineural, and the
      more specific HP term is bound on the basis of the fuller clinical description in
      the same paper rather than on this sentence.
- category: Growth
  name: Short Stature
  description: Short stature, one of the cardinal features.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:24911150
    reference_title: "Hypomorphic PCNA mutation underlies a human DNA repair disorder."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a syndrome in which the cardinal clinical features include short
      stature, hearing loss, premature aging, telangiectasia, neurodegeneration, and
      photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence
      alteration of the proliferating cell nuclear antigen (PCNA).
    explanation: Lists short stature as cardinal.
- category: Constitutional
  name: Premature Aging
  description: >-
    A prematurely aged appearance, one of the six cardinal features and the reason this
    entry carries Progeroid Syndrome among its parents. Bound to HP:0007495 Prematurely aged
    appearance rather than to the second term the deep-research report proposed alongside
    it: HP:0001025 is Urticaria, and binding it here would have asserted an unrelated
    dermatological finding. That is the report-CURIE-as-lead rule doing its work.
  phenotype_term:
    preferred_term: Prematurely aged appearance
    term:
      id: HP:0007495
      label: Prematurely aged appearance
  evidence:
  - reference: PMID:24911150
    reference_title: Hypomorphic PCNA mutation underlies a human DNA repair disorder.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The principal features included neurodegeneration, postnatal growth retardation,
      prelingual sensorineural hearing loss, premature aging, ocular and cutaneous
      telangiectasia, learning difficulties, photophobia, and photosensitivity with
      evidence of predisposition to sun-induced malignancy.
    explanation: >-
      Names premature aging among the principal features in all four affected members of
      the founding pedigree. Note the whole clinical description of this disorder rests on
      that one kindred.
- category: Neurologic
  name: Cognitive Decline
  description: >-
    Learning difficulties in childhood with cognitive decline as the patients aged. Curated
    separately from the Neurodegeneration node because the source presents it as one of the
    features characterising that degeneration rather than as a distinct process; this row
    makes the cognitive component explicit where the parent node aggregates it.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:24911150
    reference_title: Hypomorphic PCNA mutation underlies a human DNA repair disorder.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurodegeneration was a consistent feature, characterized by progressive gait
      instability, muscle weakness, foot deformity, difficulties with speech and
      swallowing, learning difficulties, and cognitive decline with advancing age.
    explanation: >-
      States both the childhood learning difficulty and the later decline, which is why the
      phenotype term carries clinical_course PROGRESSIVE.
- category: Neurologic
  name: Progressive Gait Instability
  description: >-
    Progressive gait instability, the presenting motor feature of the neurodegeneration and
    the reason this disorder sits among the ataxias clinically.
  phenotype_term:
    preferred_term: Gait ataxia
    term:
      id: HP:0002066
      label: Gait ataxia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:24911150
    reference_title: Hypomorphic PCNA mutation underlies a human DNA repair disorder.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurodegeneration was a consistent feature, characterized by progressive gait
      instability, muscle weakness, foot deformity, difficulties with speech and
      swallowing, learning difficulties, and cognitive decline with advancing age.
    explanation: >-
      Names the gait instability and its progressive character. Bound to gait ataxia because
      the disorder's cerebellar atrophy is curated here and the clinical label is ataxia,
      though the source says only "gait instability".
- category: Neurologic
  name: Muscle Weakness
  description: Muscle weakness, listed among the features characterising the neurodegeneration.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:24911150
    reference_title: Hypomorphic PCNA mutation underlies a human DNA repair disorder.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurodegeneration was a consistent feature, characterized by progressive gait
      instability, muscle weakness, foot deformity, difficulties with speech and
      swallowing, learning difficulties, and cognitive decline with advancing age.
    explanation: Names muscle weakness among the neurodegenerative features.
- category: Neurologic
  name: Dysphagia
  description: >-
    Difficulty with swallowing. Curated separately from the speech difficulty in the same
    clause because they are different functions with different clinical consequences, even
    though the source lists them together.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:24911150
    reference_title: Hypomorphic PCNA mutation underlies a human DNA repair disorder.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurodegeneration was a consistent feature, characterized by progressive gait
      instability, muscle weakness, foot deformity, difficulties with speech and
      swallowing, learning difficulties, and cognitive decline with advancing age.
    explanation: >-
      The swallowing half of the source's "difficulties with speech and swallowing". The
      source does not characterise the mechanism, so no bulbar or oesophageal claim is made.
- category: Neurologic
  name: Dysarthria
  description: Difficulty with speech, the other half of the source's speech-and-swallowing clause.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:24911150
    reference_title: Hypomorphic PCNA mutation underlies a human DNA repair disorder.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurodegeneration was a consistent feature, characterized by progressive gait
      instability, muscle weakness, foot deformity, difficulties with speech and
      swallowing, learning difficulties, and cognitive decline with advancing age.
    explanation: >-
      INDIRECT because the source says "difficulties with speech" without specifying
      dysarthria; the binding narrows to the motor-speech reading that the surrounding
      neurodegenerative and bulbar features support, and no aphasia claim is made.
- category: Skeletal
  name: Foot Deformity
  description: >-
    Foot deformity, listed among the neurodegenerative features. Bound at the general
    abnormal-foot-morphology level because the source names no specific deformity.
  phenotype_term:
    preferred_term: Abnormal foot morphology
    term:
      id: HP:0001760
      label: Abnormal foot morphology
  evidence:
  - reference: PMID:24911150
    reference_title: Hypomorphic PCNA mutation underlies a human DNA repair disorder.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurodegeneration was a consistent feature, characterized by progressive gait
      instability, muscle weakness, foot deformity, difficulties with speech and
      swallowing, learning difficulties, and cognitive decline with advancing age.
    explanation: >-
      Names the finding. It is listed among the neurodegenerative features, so a
      neurogenic rather than primary skeletal origin is implied but not stated.
- category: Ophthalmologic
  name: Photophobia
  description: >-
    Photophobia, one of the principal features and distinct from the cutaneous
    photosensitivity curated separately: one is an ocular symptom, the other a skin
    response to UV.
  phenotype_term:
    preferred_term: Photophobia
    term:
      id: HP:0000613
      label: Photophobia
  evidence:
  - reference: PMID:24911150
    reference_title: Hypomorphic PCNA mutation underlies a human DNA repair disorder.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The principal features included neurodegeneration, postnatal growth retardation,
      prelingual sensorineural hearing loss, premature aging, ocular and cutaneous
      telangiectasia, learning difficulties, photophobia, and photosensitivity with
      evidence of predisposition to sun-induced malignancy.
    explanation: Names photophobia among the principal features, separately from photosensitivity.
- category: Neoplastic
  name: Predisposition to Sun-Induced Skin Malignancy
  description: >-
    Evidence of predisposition to sun-induced malignancy, which is the expected consequence
    of a nucleotide-excision-repair defect and is what places this disorder alongside the
    NER cancer-prone syndromes. The source says "evidence of predisposition" rather than
    reporting a tumour rate, and that hedge is kept: with four affected individuals no
    frequency or relative risk can be asserted.
  phenotype_term:
    preferred_term: Neoplasm of the skin
    term:
      id: HP:0008069
      label: Neoplasm of the skin
  evidence:
  - reference: PMID:24911150
    reference_title: Hypomorphic PCNA mutation underlies a human DNA repair disorder.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The principal features included neurodegeneration, postnatal growth retardation,
      prelingual sensorineural hearing loss, premature aging, ocular and cutaneous
      telangiectasia, learning difficulties, photophobia, and photosensitivity with
      evidence of predisposition to sun-induced malignancy.
    explanation: >-
      States the predisposition with the authors' own "evidence of" qualifier, which is why
      this row asserts a predisposition rather than a malignancy frequency.
- category: Auditory
  name: Labyrinthine Dysplasia
  description: >-
    Bilateral mild labyrinthine dysplasia with mildly dilated vestibules on imaging. Worth
    curating separately from the sensorineural hearing loss because it is a structural
    inner-ear finding rather than a functional one, and a developmental malformation in a
    DNA-repair disorder is the kind of observation a reader would want to see rather than
    have folded into the hearing-loss row.
  phenotype_term:
    preferred_term: Abnormal inner ear morphology
    term:
      id: HP:0011390
      label: Abnormal inner ear morphology
  severity: MILD
  evidence:
  - reference: PMID:24911150
    reference_title: Hypomorphic PCNA mutation underlies a human DNA repair disorder.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Inner ear abnormalities included bilateral mild labyrinthine dysplasia with mildly
      dilated vestibules.
    explanation: >-
      The imaging finding, with the source's own "mild" qualifier carried into severity.
environmental:
- name: Ultraviolet radiation exposure
  description: >-
    Solar UV, the one environmental factor with a demonstrated interaction with this
    disorder's molecular defect. The pathophysiology here is not caused by exposure - the
    disease is the repair defect - but UV is what converts that defect into a visible
    cellular and cutaneous phenotype, which is why the link is EXACERBATES rather than
    TRIGGERS. Note the interaction is demonstrated in patient fibroblasts under controlled
    irradiation; no source cited here reports a dose-response in patients, so this is the
    mechanism of the exposure rather than a quantified clinical risk.
  exposure_term:
    preferred_term: exposure to ultraviolet radiation
    term:
      id: ECTO:0000006
      label: exposure to ultraviolet radiation
  influences_mechanisms:
  - target: Defective DNA Damage Response
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      UV generates the helix-distorting lesions that nucleotide excision repair exists to
      remove, so it is the challenge under which the repair deficit becomes measurable.
      Patient cells are near-normal until irradiated.
    evidence:
    - reference: PMID:24911150
      reference_title: Hypomorphic PCNA mutation underlies a human DNA repair disorder.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Ser228Ile alteration appeared to have no effect on protein levels or DNA
        replication, patient cells exhibited marked abnormalities in response to UV
        irradiation, displaying substantial reductions in both UV survival and RNA
        synthesis recovery.
      explanation: >-
        The clearest statement of the interaction: unremarkable at baseline, deficient under
        UV. It is also the sentence that keeps this an exacerbating rather than an
        initiating exposure, since the defect exists without it.
  evidence:
  - reference: PMID:24911150
    reference_title: Hypomorphic PCNA mutation underlies a human DNA repair disorder.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The principal features included neurodegeneration, postnatal growth retardation,
      prelingual sensorineural hearing loss, premature aging, ocular and cutaneous
      telangiectasia, learning difficulties, photophobia, and photosensitivity with
      evidence of predisposition to sun-induced malignancy.
    explanation: >-
      The clinical counterpart of the cellular result: photosensitivity and sun-induced
      malignancy are the patient-level consequences of UV exposure meeting this repair
      defect. INDIRECT because the sentence reports the phenotypes rather than the exposure
      relationship.
genetic:
- name: PCNA
  gene_term:
    preferred_term: PCNA
    term:
      id: hgnc:8729
      label: PCNA
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  review_notes: >-
    Proliferating cell nuclear antigen, the homotrimeric sliding clamp that encircles DNA
    and tethers replication and repair enzymes to it. Only hypomorphic biallelic alleles
    are compatible with life, so the causal allelic spectrum for this disease is
    intrinsically narrow: two missense substitutions, p.Ser228Ile and p.Cys148Ser.
  evidence:
  - reference: PMID:24911150
    reference_title: "Hypomorphic PCNA mutation underlies a human DNA repair disorder."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "PCNA is a highly conserved sliding clamp protein essential for DNA replication and repair."
    explanation: States the gene product's function and its essentiality.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Autosomal recessive. Both described alleles are homozygous in affected individuals,
    and the first was identified by homozygosity mapping in a consanguineous founder
    community, which is the ascertainment route that makes ultra-rare recessive alleles
    findable at all.
  evidence:
  - reference: PMID:24911150
    reference_title: "Hypomorphic PCNA mutation underlies a human DNA repair disorder."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a syndrome in which the cardinal clinical features include short
      stature, hearing loss, premature aging, telangiectasia, neurodegeneration, and
      photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence
      alteration of the proliferating cell nuclear antigen (PCNA).
    explanation: States the homozygous genotype of the affected individuals.
diagnosis:
- name: PCNA Sequencing
  description: >-
    Molecular confirmation is by sequencing PCNA. In practice the disorder is reached from
    a clinical suspicion of a DNA repair syndrome, since the phenotype overlaps several
    of them and none of the individual features is specific.
  evidence:
  - reference: PMID:24911150
    reference_title: "Hypomorphic PCNA mutation underlies a human DNA repair disorder."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a syndrome in which the cardinal clinical features include short
      stature, hearing loss, premature aging, telangiectasia, neurodegeneration, and
      photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence
      alteration of the proliferating cell nuclear antigen (PCNA).
    explanation: Establishes the gene that confirmatory sequencing targets.
- name: UV Sensitivity and RNA Synthesis Recovery in Patient Fibroblasts
  description: >-
    The cellular assays that characterise the disorder: reduced survival after UV and
    failure to recover RNA synthesis afterwards. These are research assays rather than
    routine diagnostics, but they are what places the disorder among the nucleotide
    excision repair diseases and would distinguish it from a purely clinical
    ataxia-telangiectasia-like picture.
  evidence:
  - reference: PMID:24911150
    reference_title: "Hypomorphic PCNA mutation underlies a human DNA repair disorder."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Interestingly, while the p.Ser228Ile alteration appeared to have no effect on protein
      levels or DNA replication, patient cells exhibited marked abnormalities in response
      to UV irradiation, displaying substantial reductions in both UV survival and RNA
      synthesis recovery.
    explanation: Names both assays and their direction in patient cells.
differential_diagnoses:
- name: Ataxia-telangiectasia (ATM)
  description: >-
    The disorder this one is named after. Both present with ataxia and telangiectasia, but
    ATM disease is a double-strand-break signalling defect with immunodeficiency, raised
    alpha-fetoprotein and a substantial malignancy risk, none of which characterises this
    entry. Photosensitivity is not a feature of ataxia-telangiectasia and is a feature
    here.
  distinguishing_features:
  - Cutaneous photosensitivity and impaired RNA synthesis recovery after UV, absent in ATM disease
  - No immunodeficiency or raised alpha-fetoprotein reported in the PCNA disorder
  - Short stature, hearing loss and premature aging are cardinal here
  - Oculomotor apraxia, common in ataxia telangiectasia, is absent in the reported PCNA patients
  evidence:
  - reference: PMID:33426167
    reference_title: "Beyond Typical Ataxia Telangiectasia: How to Identify the Ataxia Telangiectasia-Like Disorders."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, absence of telangiectasia, normal levels of alpha-fetoprotein and negative
      genetic test may direct to alternative diagnosis with similar phenotypes such as
      ataxia telangiectasia-like disorders (ATLD).
    explanation: >-
      States the clinical route by which a patient reaches this differential at all, which
      is the practical content of this row: the ATLD label is what is left when ataxia
      telangiectasia has been looked for and not found.
  - reference: PMID:24911150
    reference_title: Hypomorphic PCNA mutation underlies a human DNA repair disorder.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ser228Ile and AT, including an absence of both the immunodeficiency and oculomotor
      apraxia commonly seen in AT-affected individuals.
    explanation: >-
      The evidence for the distinguishing feature above, from the founding report rather
      than from the ATLD nosology review. It also supplies a second discriminator the row
      did not name: oculomotor apraxia, absent here and common in ataxia telangiectasia.
  - reference: PMID:24911150
    reference_title: Hypomorphic PCNA mutation underlies a human DNA repair disorder.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      normal chromosomes (untreated or gamma ray-induced; patient VI:11), alpha-fetoprotein
      (AFP) levels, Ig patterns
    explanation: >-
      Records that AFP and immunoglobulins were measured and normal, which is what makes the
      absence a finding rather than an untested assumption. INDIRECT: it is a methods-level
      list of what was normal, in one patient, not a statement about the disorder.
- name: Ataxia-telangiectasia-like disorder 1 (MRE11)
  description: >-
    Shares the clinical label and the numbering but not the mechanism: ATLD1 is caused by
    MRE11 variants and is a double-strand-break repair defect. The shared name reflects
    the era in which both were described clinically, and grouping the two by mechanism
    would be a mistake.
  distinguishing_features:
  - Caused by MRE11 rather than PCNA
  - Double-strand-break repair rather than nucleotide excision repair
  - No UV photosensitivity phenotype
  - Loss of MRE11 protein on western blot, with reduced ATM-dependent phosphorylation
  - Reported additional features not described in ATLD2, including hypergonadotropic hypogonadism and neutrophil hypersegmentation
  evidence:
  - reference: PMID:24733832
    reference_title: "Hypergonadotropic hypogonadism and hypersegmented neutrophils in a patient with ataxia-telangiectasia-like disorder: potential diagnostic clues?"
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Western blot assay demonstrated total loss of MRE11 and reduction of ATM-dependent
      phosphorylation; thus, we diagnosed ATLD.
    explanation: >-
      The laboratory signature that separates ATLD1 from this entry at the bench. Note this
      reference and the one below describe ATLD1 patients, not ATLD2 ones, and are cited
      here only for the differential - the two disorders share a name and nothing else
      mechanistically, so quoting them anywhere else in this entry would be an error.
  - reference: PMID:24733832
    reference_title: "Hypergonadotropic hypogonadism and hypersegmented neutrophils in a patient with ataxia-telangiectasia-like disorder: potential diagnostic clues?"
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a female ATLD patient presenting with hypergonadotropic hypogonadism and
      hypersegmented neutrophils, previously undescribed features in this disorder, and
      potential diagnostic clues to differentiate ATLD from other conditions.
    explanation: >-
      Proposed ATLD1 discriminators. Recorded because they are features to look for when
      the differential is open, not because they have been sought and excluded in ATLD2;
      one patient, and the authors offer them as clues rather than criteria.
  - reference: PMID:23436002
    reference_title: Clinical course of two Italian siblings with ataxia-telangiectasia-like disorder.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although the disease had early onset and the clinical picture was initially severe,
      suggesting ataxia-telangiectasia, neurological impairment, ocular motor apraxia and
      neuropsychological tests showed very slow deterioration in adult age.
    explanation: >-
      Thirty years of follow-up in ATLD1, and the closest thing either disorder has to a
      natural history. Included so the differential carries a sense of course as well as of
      mechanism; no comparable long-term series exists for ATLD2.
- name: Cockayne syndrome and other nucleotide excision repair disorders
  description: >-
    Mechanistically the closer relatives. Cockayne syndrome, UV-sensitive syndrome,
    xeroderma pigmentosum and trichothiodystrophy share the photosensitivity and the
    RNA-synthesis-recovery defect, and the founding report frames this disorder against
    exactly that set. Distinguishing them is a molecular rather than a clinical exercise.
  distinguishing_features:
  - Caused by PCNA rather than by a core NER gene
  - Telangiectasia is prominent, which is not typical of the classical NER syndromes
  evidence:
  - reference: PMID:24911150
    reference_title: "Hypomorphic PCNA mutation underlies a human DNA repair disorder."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    snippet: >-
      Numerous human disorders, including Cockayne syndrome, UV-sensitive syndrome,
      xeroderma pigmentosum, and trichothiodystrophy, result from the mutation of genes
      encoding molecules important for nucleotide excision repair.
    explanation: >-
      Names the disorder class this entry is framed against, in the founding report's own
      opening sentence.
discussions:
- discussion_id: why_the_phenotype_is_neurological
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Defective DNA Damage Response
  - phenotypes#
  prompt: >-
    PCNA is required in every dividing cell. Why is a hypomorphic PCNA allele a
    neurodegenerative disease rather than a proliferative or a cancer-predisposition one?
  rationale: >-
    This is the question the pathograph does not answer. The chain runs from the allele to
    a repair defect that is demonstrable in patient fibroblasts, and then to a phenotype
    that is overwhelmingly cerebellar and neurodevelopmental. Nothing in the sources cited
    here explains the tissue selectivity.

    A candidate exists and is worth recording so that it can be tested rather than assumed:
    global-genome nucleotide excision repair is constitutively weaker in neurons and
    astrocytes than in fibroblasts, and the amount of PCNA recruited to UV-damage sites is
    correspondingly lower in those cells. If neural cells already operate near the lower
    limit of what the pathway can deliver, a hypomorphic clamp would bite there first while
    dividing tissues absorb it. The measurement supporting that is rat primary culture on
    wild-type cells, so it is a hypothesis about the general biology and not an observation
    about this disease.

    Two things would move it. A patient-derived neural model, of which none is reported
    here, and a comparison of chromatin-bound PCNA between patient neural cells and patient
    fibroblasts, which is measurable with the assay the founding reports already use.
  evidence:
  - reference: PMID:17236820
    reference_title: Neurons and astrocytes exhibit lower activities of global genome nucleotide excision repair than do fibroblasts.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The results demonstrate that both neurons and astrocytes have significantly lower NER
      capabilities than fibroblasts.
    explanation: >-
      The candidate explanation for the tissue selectivity. INDIRECT and MODEL_ORGANISM: rat
      primary cultures of wild-type cells, so it establishes a baseline difference between
      cell types rather than anything about this disease.
  - reference: PMID:17236820
    reference_title: Neurons and astrocytes exhibit lower activities of global genome nucleotide excision repair than do fibroblasts.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      That result was consistent with the finding that levels of an NER-related protein
      (proliferating cell nuclear antigen, PCNA) recruited at the localized UV-damage sites
      were lower in neurons and in astrocytes than in fibroblasts.
    explanation: >-
      Curated separately because it is the part that names PCNA specifically, which is what
      makes the candidate relevant to this disease rather than to NER disorders generally.
- discussion_id: untested_epigenetic_branch
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Impaired PCNA Client Protein Binding
  prompt: >-
    DNMT1 is among the PIP-box clients whose binding is impaired. Does ATLD2 carry a
    maintenance-methylation defect, and has anyone looked?
  rationale: >-
    The client-binding node records that DNMT1 is affected alongside the repair enzymes,
    and DNMT1 is how CpG methylation patterns survive replication. If clamp-dependent
    loading of DNMT1 is impaired in patient cells, the disease would have an epigenetic arm
    in addition to a repair arm, which would be a different kind of disease from the one
    this entry describes.

    The supporting biology is established outside this disease: DNMT1 is targeted to
    replication sites through a PCNA-binding domain, with a second PCNA-independent route
    through UHRF1/Np95 binding hemimethylated DNA. Two routes matter here, because a defect
    in the PCNA-dependent one need not abolish maintenance methylation - which is a reason
    the branch might be real and still hard to see.

    No source cited here reports methylation in ATLD2 patient cells, so this is an untested
    branch and not a suppressed finding. It is recorded rather than modelled: putting a
    methylation node in the pathograph would assert a claim nobody has made.
  evidence:
  - reference: PMID:23535145
    reference_title: Dissection of cell cycle-dependent dynamics of Dnmt1 by FRAP and diffusion-coupled modeling.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Two subdomains, the proliferating cell nuclear antigen (PCNA)-binding domain (PBD) and
      the targeting sequence (TS) domain, target Dnmt1 to the replication sites in S phase.
    explanation: >-
      Establishes the PCNA-dependent route the gap is about, and that it is one of two. Mouse
      somatic cells and wild-type PCNA, so it says nothing about the disease variant.
  - reference: PMID:17994007
    reference_title: The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Np95 forms complexes with Dnmt1 and mediates the loading of Dnmt1 to replicating
      heterochromatic regions.
    explanation: >-
      The parallel PCNA-independent loading route, and the reason a PCNA-side defect would
      not necessarily abolish maintenance methylation. Recorded because it bears on how hard
      the branch would be to detect, not because it supports the branch existing.
- discussion_id: allele_specific_mechanism
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Impaired PCNA Client Protein Binding
  - pathophysiology#Reduced PCNA Thermostability
  - mechanistic_hypotheses#reduced_functional_clamp_pool
  prompt: >-
    Do the two causal PCNA alleles produce the same disease by the same route, or by two
    different routes that happen to converge on the clinical phenotype?
  rationale: >-
    p.Ser228Ile impairs client binding across most PIP-box partners; p.Cys148Ser has
    wild-type-like structure and wild-type-like partner affinity and causes the same
    disease. The only property the alleles share is reduced thermostability, which points
    at the amount of functional clamp rather than at any lost interaction. But the
    inference is not closed: no experiment has shown that lowering PCNA levels by an
    unrelated means reproduces the cellular phenotype, and the S228I cells were explicitly
    reported to have normal PCNA protein levels, so a shared level-based mechanism has to
    explain how that allele produces the disease without a measured level change.
    Resolving this determines whether evidence gathered on one allele can be read as
    evidence about the disease, which is currently assumed throughout the literature and
    throughout this entry.
  evidence:
  - reference: PMID:36990216
    reference_title: "A thermosensitive PCNA allele underlies an ataxia-telangiectasia-like disorder."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "Unlike PCNA-S228I, PCNA-C148S has WT-like structure and affinity toward partners."
    explanation: The dissociation between the two alleles that this gap is about.
  - reference: PMID:24911150
    reference_title: "Hypomorphic PCNA mutation underlies a human DNA repair disorder."
    supports: REFUTE
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Interestingly, while the p.Ser228Ile alteration appeared to have no effect on protein
      levels or DNA replication, patient cells exhibited marked abnormalities in response
      to UV irradiation, displaying substantial reductions in both UV survival and RNA
      synthesis recovery.
    explanation: >-
      Recorded as REFUTE against the unified clamp-level account. If S228I cells have
      normal PCNA protein levels, then reduced clamp availability cannot be the whole
      mechanism for that allele, whatever the thermostability assays show in vitro.
- discussion_id: cellular_defect_to_clinical_severity
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Defective DNA Damage Response
  - phenotypes#Neurodegeneration
  prompt: >-
    Why does a repair defect that produces only subtle changes in undamaged cells produce
    progressive neurodegeneration in the whole organism?
  rationale: >-
    The in vitro effects of the S228I allele on client binding are dramatic, and yet the
    downstream cellular consequences are described as subtle: p21 and Cdt1 stability are
    only minimally altered in patient cells, and DNA replication is unaffected. The
    authors of that work explicitly frame the gap - large biochemical perturbation, small
    cellular effect - and propose that the small effects accumulate. Nothing has tested
    that in neural tissue, and no model system for this disorder has been reported at all,
    so the step from a mild fibroblast phenotype to cerebellar atrophy is currently an
    argument rather than a finding.
  evidence:
  - reference: PMID:28073635
    reference_title: "PCNA dependent cellular activities tolerate dramatic perturbations in PCNA client interactions."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Despite the dramatic in vitro effects of the PARD mutation on PIP-degron binding,
      there are only minor alterations to the stability of p21 and Cdt1 in cells from
      affected individuals.
    explanation: >-
      States the disproportion between the biochemical and the cellular effect, which is
      what this gap is about. The paper's own title makes the same point.
notes: >-
  Lump/split decision: DISEASE. MONDO:0014399 names one entity with one conserved
  pathograph - biallelic hypomorphic PCNA, a damage-response defect, and a
  progeroid-neurodegenerative-photosensitive syndrome - and the stub is retired
  accordingly. Neither MONDO parent (ataxia-telangiectasia-like disorder MONDO:0011457,
  DNA repair disease MONDO:0021190) is curated, so nothing here duplicates an existing
  entry. ATLD1 (MRE11) is a separate disease and is carried here only as a differential.

  The two alleles are curated as one disease with two mechanistic hypotheses rather than
  as two diseases or as one chain. That is a deliberate call. They are clinically the same
  syndrome and both are called PARD in the literature, so splitting would be wrong; but
  the published molecular accounts of them are incompatible in a way that a single chain
  would have to paper over, so lumping them into one mechanism would also be wrong. The
  hypothesis groups and the allele_specific_mechanism knowledge gap are how the entry says
  both things at once.

  A limitation of the curation worth naming, because it affects how every evidence item
  here should be read: dismech's EvidenceItem has no slot for which allele an experiment
  was performed on. In a disease where the two causal alleles demonstrably differ in
  molecular consequence, that matters, and the only place this entry can record it is in
  free-text explanation fields. Where an evidence item is allele-specific, its explanation
  says so explicitly.

  Sample sizes are similarly carried in prose rather than in structure. The entire
  clinically described population of the founding report is four individuals from one
  pedigree, and cerebellar atrophy rests on imaging in one of them. Where a snippet could
  be chosen either with or without its denominator, this entry chose the one that carries
  it.

  No treatments section. No disease-modifying or symptomatic treatment specific to this
  disorder is reported in the cited literature, and inventing a supportive-care row would
  assert clinical content that does not exist. Sun protection follows from the
  photosensitivity by the same logic as in the other NER disorders but is not stated for
  this disease in any source cited here, so it is not curated as a treatment.

  No animal or experimental models. None is reported for this disorder. This is a real
  gap rather than an unsearched one and is recorded in the second knowledge gap.

  The deep-research report generated for this entry is committed alongside it under
  research/. Reference selection and every snippet were taken from the fetched reference
  cache rather than from the report. It passes just preflight-dr against MONDO:0014399 -
  PCNA is named 72 times, and the OMIM number in the report matches MONDO's - which is
  worth stating because the sibling KIDAR entry curated in the same run had to discard its
  report entirely for naming the wrong disease.

  On the report's references. It cites fourteen; thirteen are cited here, and the two that
  are not are deliberate. PMID:38814467 reviews the bacterial beta-clamp - useful background
  on sliding clamps as a protein family, and not evidence about a human disease.
  PMID:23622410 is a general review of progressive cerebellar atrophy in childhood that
  mentions ATLD in a list; citing it would add a reference and no claim. Neither cache file
  is committed, since this entry does not cite them. The disease-specific weight is carried
  by PMID:24911150, PMID:28073635 and PMID:36990216, which are cited throughout.

  Three of the report's references describe MRE11-related ATLD1 rather than this disease.
  They are cited here only in the ATLD1 differential row, and the explanations on those
  items say so. The two disorders share a name and a numbering and nothing mechanistic, so
  quoting an ATLD1 cohort anywhere else in this entry would be exactly the wrong-entity
  error the KIDAR entry in this run documents - reached by shared name rather than by
  shared gene.
📚

References & Deep Research

References

13
PMID:24911150
Hypomorphic PCNA mutation underlies a human DNA repair disorder.
No top-level findings curated for this source.
PMID:28073635
PCNA dependent cellular activities tolerate dramatic perturbations in PCNA client interactions.
No top-level findings curated for this source.
PMID:36990216
A thermosensitive PCNA allele underlies an ataxia-telangiectasia-like disorder.
No top-level findings curated for this source.
PMID:17236820
Neurons and astrocytes exhibit lower activities of global genome nucleotide excision repair than do fibroblasts.
No top-level findings curated for this source.
PMID:17994007
The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA.
No top-level findings curated for this source.
PMID:23535145
Dissection of cell cycle-dependent dynamics of Dnmt1 by FRAP and diffusion-coupled modeling.
No top-level findings curated for this source.
PMID:25972089
p21 Exploits Residue Tyr151 as a Tether for High-Affinity PCNA Binding.
No top-level findings curated for this source.
PMID:26688547
A Disease-Causing Variant in PCNA Disrupts a Promiscuous Protein Binding Site.
No top-level findings curated for this source.
PMID:33426167
Beyond Typical Ataxia Telangiectasia: How to Identify the Ataxia Telangiectasia-Like Disorders.
No top-level findings curated for this source.
PMID:33984330
Unlocking the PIP-box: A peptide library reveals interactions that drive high-affinity binding to human PCNA.
No top-level findings curated for this source.
PMID:37511614
A FRET-Based Assay for the Identification of PCNA Inhibitors.
No top-level findings curated for this source.
PMID:23436002
Clinical course of two Italian siblings with ataxia-telangiectasia-like disorder.
No top-level findings curated for this source.
PMID:24733832
Hypergonadotropic hypogonadism and hypersegmented neutrophils in a patient with ataxia-telangiectasia-like disorder: potential diagnostic clues?
No top-level findings curated for this source.

Deep Research

1

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 (3)

Record notes

Lump/split decision: DISEASE. MONDO:0014399 names one entity with one conserved pathograph - biallelic hypomorphic PCNA, a damage-response defect, and a progeroid-neurodegenerative-photosensitive syndrome - and the stub is retired accordingly. Neither MONDO parent (ataxia-telangiectasia-like disorder MONDO:0011457, DNA repair disease MONDO:0021190) is curated, so nothing here duplicates an existing entry. ATLD1 (MRE11) is a separate disease and is carried here only as a differential. The two alleles are curated as one disease with two mechanistic hypotheses rather than as two diseases or as one chain. That is a deliberate call. They are clinically the same syndrome and both are called PARD in the literature, so splitting would be wrong; but the published molecular accounts of them are incompatible in a way that a single chain would have to paper over, so lumping them into one mechanism would also be wrong. The hypothesis groups and the allele_specific_mechanism knowledge gap are how the entry says both things at once. A limitation of the curation worth naming, because it affects how every evidence item here should be read: dismech's EvidenceItem has no slot for which allele an experiment was performed on. In a disease where the two causal alleles demonstrably differ in molecular consequence, that matters, and the only place this entry can record it is in free-text explanation fields. Where an evidence item is allele-specific, its explanation says so explicitly. Sample sizes are similarly carried in prose rather than in structure. The entire clinically described population of the founding report is four individuals from one pedigree, and cerebellar atrophy rests on imaging in one of them. Where a snippet could be chosen either with or without its denominator, this entry chose the one that carries it. No treatments section. No disease-modifying or symptomatic treatment specific to this disorder is reported in the cited literature, and inventing a supportive-care row would assert clinical content that does not exist. Sun protection follows from the photosensitivity by the same logic as in the other NER disorders but is not stated for this disease in any source cited here, so it is not curated as a treatment. No animal or experimental models. None is reported for this disorder. This is a real gap rather than an unsearched one and is recorded in the second knowledge gap. The deep-research report generated for this entry is committed alongside it under research/. Reference selection and every snippet were taken from the fetched reference cache rather than from the report. It passes just preflight-dr against MONDO:0014399 - PCNA is named 72 times, and the OMIM number in the report matches MONDO's - which is worth stating because the sibling KIDAR entry curated in the same run had to discard its report entirely for naming the wrong disease. On the report's references. It cites fourteen; thirteen are cited here, and the two that are not are deliberate. PMID:38814467 reviews the bacterial beta-clamp - useful background on sliding clamps as a protein family, and not evidence about a human disease. PMID:23622410 is a general review of progressive cerebellar atrophy in childhood that mentions ATLD in a list; citing it would add a reference and no claim. Neither cache file is committed, since this entry does not cite them. The disease-specific weight is carried by PMID:24911150, PMID:28073635 and PMID:36990216, which are cited throughout. Three of the report's references describe MRE11-related ATLD1 rather than this disease. They are cited here only in the ATLD1 differential row, and the explanations on those items say so. The two disorders share a name and a numbering and nothing mechanistic, so quoting an ATLD1 cohort anywhere else in this entry would be exactly the wrong-entity error the KIDAR entry in this run documents - reached by shared name rather than by shared gene.

Review round 1: add the missing cardinal phenotype, mine the founding report harder, link UV · 2026-09-10T19:38:02Z · View source

Round 1 of review on PR #11641. Both blocking items and all four suggestions, in one push. Snippets 48 to 62; phenotypes 7 to 18. BLOCKING 1, premature aging. The reviewer is right and the miss is embarrassing in a specific way: the entry quotes the six-cardinal-features sentence six times, curates five of the six, declares Progeroid Syndrome among its parents, and asserts in a differential row that premature aging is cardinal here. Every signal pointed at the gap except the phenotypes list itself. One correction to the finding. Both the deep-research report and the review propose binding either HP:0007495 or HP:0001025. HP:0001025 is Urticaria. Binding it would have asserted an unrelated dermatological finding in a progeroid disorder, and it would have validated cleanly, because term validation checks that a label matches its CURIE and not that the concept matches the claim. Bound to HP:0007495 Prematurely aged appearance, with the reasoning recorded in the phenotype description so the next reader does not repeat the suggestion. This is the CLAUDE.md rule about a report's CURIE being a lead rather than an answer, and it survived one review round before being caught. BLOCKING 2, references. PMID:23436002 and PMID:24733832 were cited in the ATLD1 differential but absent from the top-level references block. Added with titles copied from the cache frontmatter. SUGGESTIONS, all taken. Nine further phenotypes from the founding report, which is the only clinical source this disorder has and was already committed here: cognitive decline, progressive gait instability, muscle weakness, dysphagia, dysarthria, foot deformity, photophobia, predisposition to sun-induced skin malignancy, and labyrinthine dysplasia. Three curation notes worth recording. Dysphagia and dysarthria are split from the source's single speech-and-swallowing clause because they are different functions with different consequences. Dysarthria is graded INDIRECT since the source says difficulties with speech without specifying a motor-speech deficit. The malignancy row asserts a predisposition rather than a rate, keeping the authors' evidence of qualifier, because four affected individuals cannot support a frequency. The unevidenced distinguishing feature is now evidenced. The ATM row asserted no immunodeficiency or raised alpha-fetoprotein with only a nosology review cited, which does not carry it. The founding report does, in two places: the absence sentence, and the methods-level list confirming AFP and immunoglobulins were measured and normal. The second matters because it turns an absence into a finding rather than an untested assumption. The same sentence supplied a discriminator the row had not named, oculomotor apraxia, now added. UV is curated as an environmental entry with influences_mechanisms to the repair node, environmental_effect EXACERBATES rather than TRIGGERS. The disease is the repair defect; UV is what makes it visible. The entry says so explicitly and notes the interaction is demonstrated in patient fibroblasts under controlled irradiation, with no dose-response reported in patients. Validation: schema clean, terms clean, 62 of 62 snippets verified, and entity refs, duplicate keys, causal targets, enum values and qualifier terms all clean.

Consume the deep-research references before opening the PR · 2026-09-10T18:52:05Z · View source

Pre-PR pass over the deep-research report, done before opening the PR rather than after review. The first draft cited 3 of the 14 references the report offers. That is the same under-consumption pattern the reviewers flagged on all four sibling PRs in this claim run (#11619, #11621, #11622, #11630), so it was worth fixing here before a reviewer had to. Eleven are now cited and verified snippets went 33 to 48. Reading the rest changed content rather than padding it. PMID:26688547 was the keystone omission: the crystal structure of the S228I variant. It shows the client-binding pocket itself is remodelled by a large conformational change, which makes the interaction defect a property of the clamp rather than of any one partner. It independently confirms the p21 exception the entry had already recorded from a different group and method, and it explains why the defect is selective rather than uniform - the remodelled pocket can still flex to accommodate some ligands. PMID:37511614 is a second laboratory reaching the C148S result by FRET, intrinsic tryptophan fluorescence, DSF and AF4: no partner-affinity effect, impaired stability, and a mechanism the founding report did not name, increased aggregation. That takes the EMERGING reduced_functional_clamp_pool hypothesis from one group's assay to two, and the aggregation finding bears on how the thermostability node should be read - a clamp that aggregates leaves the functional pool as surely as one that unfolds. PMID:25972089 supplies a candidate reason p21 in particular survives the pocket remodelling: it is an atypical PIP-box with the highest known PCNA affinity, tethered by a tyrosine that most partners do not carry. Graded INDIRECT because the work is on wild-type PCNA and does not test the variant. PMID:33984330 sets the scale the selectivity must be read against - native PIP-box affinities already span four orders of magnitude, so a pocket change will not affect all partners equally even before any structural accommodation. Two knowledge gaps added, both acting on report findings the first draft had left alone. why_the_phenotype_is_neurological asks the question the pathograph does not answer: PCNA is required in every dividing cell, so why is this a cerebellar disease. PMID:17236820 supplies a testable candidate, that global-genome NER and PCNA recruitment to UV-damage sites are both constitutively lower in neurons and astrocytes than in fibroblasts, so neural cells may already sit near the lower limit of what the pathway delivers. It is rat primary culture on wild-type cells, so it is graded INDIRECT and MODEL_ORGANISM and recorded as a hypothesis about general biology rather than an observation about this disease. The gap names the two measurements that would move it. untested_epigenetic_branch records that DNMT1 is among the impaired clients and that nobody has looked for a methylation defect in patient cells. PMID:23535145 establishes the PCNA-dependent loading route and PMID:17994007 the parallel UHRF1/Np95 route; the second matters because a PCNA-side defect need not abolish maintenance methylation, so the branch could be real and still hard to detect. Recorded rather than modelled - putting a methylation node in the pathograph would assert a claim no source makes. Three of the report's references describe MRE11-related ATLD1, a different gene and a different repair pathway sharing only the clinical name and the numbering. They are cited only in the ATLD1 differential row, their explanations say so, and notes records why quoting them anywhere else would be the same wrong-entity error the sibling KIDAR entry documents, reached through a shared name rather than a shared gene. Three further references are deliberately uncited and notes says which and why: a bacterial beta-clamp review, which is not evidence about a human disease, and a general cerebellar-atrophy review that mentions ATLD in a list and would add a citation without a claim. Also: the links.issues field on the CREATE record was empty and is now filled with issue 11610, read back from the API. Three of the four sibling PRs in this run had a wrong issue number in a history record because the numbers were written from working memory of a contiguous block; that is why this one was looked up. Validation: schema clean, terms clean, 48 of 48 snippets verified, and entity refs, duplicate keys, causal targets, enum values and qualifier terms all clean.

OpenScientist ▸
Key Findings
openscientist-autonomous 14 citations 2026-09-10T18:38:46.539209

Key Findings

Finding 1 — ATLD2/PARD is caused by biallelic hypomorphic PCNA missense variants

ATLD2 is a monogenic disorder of the PCNA gene. The original description by Baple et al. (2014) identified a homozygous missense variant, c.683C>T (p.Ser228Ile), in an Amish kindred, establishing PCNA as the causal gene: "resulting from a homozygous missense (p.Ser228Ile) sequence alteration of the proliferating cell nuclear antigen (PCNA)" PMID: 24911150. Nearly a decade later, Magrino et al. (2023) reported a second, independent causal allele: "we report a second PCNA substitution (C148S) that also causes PARD" PMID: 36990216.

Both variants are hypomorphic (partial loss of function) rather than null. This is a mechanistic necessity: PCNA is essential for DNA replication in every proliferating cell, and complete loss of function is incompatible with embryonic development. The disease alleles therefore retain sufficient replicative clamp activity to permit survival while degrading the fidelity of DNA-maintenance functions. This places ATLD2 in the family of "essential-gene hypomorph" disorders, where the surviving phenotype reflects the most partner-sensitive and repair-dependent tissues rather than global replication failure.

  • Variant 1: NM_002592.2:c.683C>T, p.(Ser228Ile) — Amish founder allele; missense; germline; classified pathogenic.
  • Variant 2: p.(Cys148Ser) — second reported causal missense allele; missense; germline; pathogenic.

Finding 2 — Cardinal clinical phenotype

The cardinal features of ATLD2/PARD were enumerated by Baple et al. (2014): "the cardinal clinical features include short stature, hearing loss, premature aging, telangiectasia, neurodegeneration, and photosensitivity" PMID: 24911150. The disorder therefore straddles two clinical categories — the DNA-repair "progeroid/photosensitivity" spectrum (Cockayne syndrome, xeroderma pigmentosum) and the ataxia-telangiectasia spectrum — and this hybrid presentation is itself a diagnostic clue.

Suggested HPO terms for the phenotypic spectrum:

Phenotype HPO term Type Onset Course
Short stature HP:0004322 Physical manifestation Childhood Stable/constitutional
Sensorineural hearing loss HP:0000407 Clinical sign / lab (audiometry) Childhood Progressive
Premature aging / progeroid appearance HP:0007495 / HP:0001025 Physical manifestation Childhood–adult Progressive
Telangiectasia HP:0001009 Clinical sign Childhood Progressive
Cerebellar ataxia / neurodegeneration HP:0001251 / HP:0002180 Symptom / sign Childhood Progressive
Cutaneous photosensitivity / UV sensitivity HP:0000992 Clinical sign Childhood Chronic

Finding 3 — Molecular mechanism: impaired partner interactions and defective NER despite normal bulk replication

The defining mechanistic insight is that the disease variants uncouple PCNA's replicative function from its repair function. Baple et al. (2014) showed that p.Ser228Ile had no effect on PCNA protein levels or DNA replication, yet patient cells "exhibited marked abnormalities in response to UV irradiation, displaying substantial reductions in both UV survival and RNA synthesis recovery" PMID: 24911150. Reduced RNA-synthesis recovery after UV is a classic hallmark of defective transcription-coupled nucleotide-excision repair. The same study localized the biochemical lesion to partner binding: "The p.Ser228Ile change also profoundly altered PCNA's interaction with Flap endonuclease 1 and DNA Ligase 1."

Magrino et al. (2023) added a complementary and unifying dimension. The C148S variant, unlike S228I, has wild-type-like structure and partner affinity in vitro, yet it destabilizes the protein: "The stability defect of both PARD variants indicates that PCNA levels are likely an important driver of PARD disease" PMID: 36990216. Thus two mechanistically distinct alleles converge on the same functional endpoint — insufficient functional PCNA at sites of DNA repair — either by remodeling the partner-binding pocket (S228I) or by reducing the steady-state pool of chromatin-competent clamp (C148S, and to a degree S228I).

Relevant GO biological-process terms: nucleotide-excision repair (GO:0006289), transcription-coupled nucleotide-excision repair (GO:0006283), DNA replication (GO:0006260), base-excision repair (GO:0006284, via FEN1/LIG1), DNA ligation (GO:0006266).

Finding 4 — PCNA is a sliding-clamp interaction hub coordinating >200 PIP-box partners

The vulnerability of PCNA to selective, partner-disrupting mutation follows from its biology as a promiscuous hub. Horsfall et al. (2021) established that human PCNA "interacts with over 200 proteins through a conserved binding motif, the PIP-box, to orchestrate DNA replication and repair" PMID: 33984330. Because all these partners compete for a small, overlapping surface, a single amino-acid change in or near that surface can re-weight the entire interactome — sparing some clients while excluding others. This "hub fragility" explains how a variant can leave replication intact while dismantling repair.

Suggested GO cellular-component terms: PCNA clamp / PCNA-containing complex (GO:0043626), nucleoplasm (GO:0005654), replication fork (GO:0005657), site of DNA damage (GO:0090734).

Finding 5 — Structural basis: S228I produces a large conformational change that transforms the client-binding pocket

Duffy, Hilbert and Kelch (2016) solved the crystal structure of PCNA–S228I and revealed the physical mechanism behind the selective binding defect. The mutation lies near the site where most PCNA partners dock, and the structure "reveals a large conformational change that dramatically transforms the binding pocket for PCNA client proteins" PMID: 26688547. Critically, the effect is client-selective: the change "markedly alters the binding energetics for some client proteins, while another, p21(CIP1), is only mildly affected." This selectivity — a remodeled pocket that repels repair partners such as FEN1/LIG1 but still accommodates the high-affinity p21 PIP-box — provides the structural explanation for the finding that replication and cell-cycle control are largely preserved while repair collapses. The plasticity of the p21 PIP-box interaction with PCNA, mediated by Tyr151, has been characterized separately and underscores how differing partners tolerate pocket changes to differing degrees PMID: 25972089.

Finding 6 — ATLD2 is one of several autosomal-recessive DNA-repair ataxias, distinguished from AT and ATLD1

Raslan et al. (2021) framed the nosology: ataxia-telangiectasia-like disorders are autosomal-recessive diseases that share clinical and pathophysiological features with classical ataxia-telangiectasia but are genetically distinct. Diagnostically, "absence of telangiectasia, normal levels of alpha-fetoprotein and negative genetic test may direct to alternative diagnosis with similar phenotypes such as ataxia telangiectasia-like disorders (ATLD)" PMID: 33426167. Within this family, ATLD1 is caused by MRE11 mutations and ATLD2 by PCNA. Supporting clinical literature on the broader ATLD/DNA-repair-ataxia spectrum documents progressive cerebellar ataxia, oculomotor apraxia, cognitive impairment, and cerebellar atrophy on MRI PMID: 24733832, PMID: 23436002, PMID: 23622410.

Finding 7 — Thermolability is a unifying disease mechanism; patient cells show temperature-dependent, UV-sensitive phenotypes

Magrino et al. (2023) demonstrated that the C148S variant has near-normal structure and affinity yet a thermostability defect, and that "patient-derived cells homozygous for the C148S allele exhibit low levels of chromatin-bound PCNA and display temperature-dependent phenotypes" PMID: 36990216. Combined with the UV-sensitivity of S228I patient cells (Finding 3), thermolability emerges as a unifying theme: reduced protein stability lowers the effective concentration of functional clamp available for repair. Hardebeck et al. (2023), in the course of developing a PCNA-inhibitor assay, framed the disease succinctly: "ATLD2 is a neurodegenerative disease based on defects in DNA repair due to an impaired PCNA" PMID: 37511614.

Finding 8 — PCNA couples DNMT1 to replication sites: a plausible but untested epigenetic branch

Beyond canonical repair, PCNA is the S-phase docking platform for the maintenance-methylation machinery. Schneider et al. (2013) showed that DNMT1's "proliferating cell nuclear antigen (PCNA)-binding domain (PBD) and the targeting sequence (TS) domain, target Dnmt1 to the replication sites in S phase" PMID: 23535145. Because DNMT1 recruitment depends on PCNA, hypomorphic PCNA could in principle perturb the fidelity of maintenance DNA methylation during replication — an epigenetic branch that is mechanistically plausible but has not been directly demonstrated in ATLD2 patient tissues. This is flagged as an inference, not an established mechanism. The parallel UHRF1/Np95 pathway that reinforces DNMT1 loading onto hemimethylated DNA provides additional context for how maintenance methylation is coordinated at the replication fork PMID: 17994007.

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

  1. Biallelic hypomorphic PCNA missense variant (p.Ser228Ile or p.Cys148Ser) is inherited in an autosomal-recessive manner — the initiating germline lesion.
  2. This leads to an altered PCNA protein: S228I undergoes a large conformational change that remodels the client-binding pocket (demonstrated, [PMID: 26688547]); C148S is near-normal in structure but thermolabile (demonstrated, [PMID: 36990216]).
  3. The altered protein results in reduced PCNA thermostability and, for both alleles, lower levels of chromatin-bound PCNA — i.e., a smaller effective pool of functional clamp at DNA (demonstrated, [PMID: 36990216]).
  4. In parallel, the S228I pocket change results in selectively weakened binding of repair partners FEN1 and DNA Ligase 1, while sparing p21 and bulk replication (demonstrated, [PMID: 24911150]; [PMID: 26688547]).
  5. Reduced repair-partner recruitment leads to defective nucleotide-excision repair and transcription-coupled repair, evidenced by reduced UV survival and impaired RNA-synthesis recovery in patient cells (demonstrated, [PMID: 24911150]).
  6. Defective repair results in accumulation of unrepaired DNA damage (endogenous and UV-induced) in cells — inferred from the repair defect.
  7. Branch A (neural): Post-mitotic neurons — which have intrinsically low NER capacity and cannot dilute damage by division [PMID: 17236820] — accumulate damage and lead to progressive cerebellar neurodegeneration and ataxia (neuronal vulnerability demonstrated in general; cerebellar tropism in ATLD2 inferred).
  8. Branch B (cutaneous): UV-hypersensitive skin leads to photosensitivity and telangiectasia.
  9. Branch C (systemic/progeroid): Genome-maintenance failure in dividing and aging tissues leads to short stature, sensorineural hearing loss, and premature aging.
  10. Branch D (epigenetic, inferred only): Impaired PCNA-dependent recruitment of DNMT1 to replication sites could perturb maintenance DNA methylation [PMID: 23535145] — not demonstrated in patients.

Schematic

  Biallelic PCNA hypomorph (S228I / C148S)
 │
┌────────┴─────────┐
   S228I: pocket        C148S: thermolabile
   conformational       (WT-like structure)
   change                    │
└────────┬───────────┘
 ▼
   ↓ chromatin-bound / functional PCNA
   + selective loss of FEN1 / LIG1 binding
 │
 ▼
   Defective NER / transcription-coupled repair
   (↓UV survival, ↓RNA-synthesis recovery)
 │
 ▼
Accumulated DNA damage
 │
   ┌─────────────┼─────────────┬───────────────┐
   ▼             ▼             ▼               ▼
Neurons      Skin (UV)     Growth/aging    (Epigenetic?
→ cerebellar → photo-      → short stature   DNMT1 mis-
  ataxia,      sensitivity,  hearing loss,   loading —
  neuro-       telangiec-    premature       INFERRED,
  degeneration tasia         aging           untested)

Upstream vs downstream

  • Upstream (cause): the PCNA genotype and its biophysical consequences (pocket remodeling, thermolability, reduced chromatin loading, lost partner binding).
  • Downstream (effect): repair failure → DNA-damage accumulation → tissue-specific degeneration → the clinical phenotype.

Cell types (CL) implicated: cerebellar neuron / Purkinje cell (CL:0000121), neuron (CL:0000540), astrocyte (CL:0000127), fibroblast (CL:0000057, the principal experimental cell type), keratinocyte (CL:0000312, UV target). Anatomy (UBERON): cerebellum (UBERON:0002037), central nervous system (UBERON:0001017), skin (UBERON:0002097), cochlea/inner ear (UBERON:0001844). Subcellular (GO CC): nucleus (GO:0005634), replication fork (GO:0005657), sites of DNA damage (GO:0090734).

Section-by-Section Synthesis

1. Disease Information

ATLD2/PARD is an ultra-rare autosomal-recessive multisystem DNA-repair disorder. Identifiers: MONDO:0014399, OMIM #615919, gene PCNA (HGNC:8729). Synonyms: PCNA-associated DNA repair disorder (PARD), ataxia-telangiectasia-like disorder 2. Knowledge is derived from aggregated disease-level resources (OMIM, Orphanet) and a small number of primary reports describing individual patients/kindreds (Amish S228I cohort; C148S cases), not from large EHR datasets.

2. Etiology

Causal factor: genetic — biallelic hypomorphic missense variants in PCNA. Genetic risk factor: carriage of two pathogenic PCNA alleles; in the Amish population, a founder effect concentrates the S228I allele, and consanguinity/endogamy raises homozygosity risk. Environmental modifier: UV/sunlight exposure exacerbates the cutaneous photosensitivity component (a gene–environment interaction: an inherited repair defect renders UV-induced lesions pathogenic). No protective genetic or environmental factors have been established. Sun avoidance is the only plausible environmental risk-reduction lever.

3. Phenotypes

See Finding 2 table. All features are childhood-onset, progressive for the neurodegenerative and sensory components, and constitutional for short stature. Frequencies are qualitative given the tiny patient population; cardinal features were consistent across the original Amish kindred. Quality-of-life impact is dominated by progressive ataxia (mobility, independence), hearing loss (communication), and the psychosocial burden of a progeroid, multisystem, incurable condition.

4. Genetic / Molecular Information

Causal gene: PCNA (chromosome 20p12.3). Variants: c.683C>T p.(Ser228Ile) and p.(Cys148Ser); both missense, germline, pathogenic; functional consequence is partial loss of function (hypomorph) via pocket remodeling (S228I) and reduced thermostability/chromatin loading (both). Population allele frequency is vanishingly rare in gnomAD (consistent with an ultra-rare recessive disorder); S228I is enriched only within the Amish founder population. No modifier genes, chromosomal abnormalities, or aneuploidy are implicated. A PCNA-dependent epigenetic (DNMT1/maintenance-methylation) branch is plausible but untested.

5. Environmental Information

No infectious or toxic etiology. The only relevant environmental factor is UV radiation, which converts the underlying NER defect into clinical photosensitivity. No lifestyle or occupational exposures are established causes.

6. Mechanism / Pathophysiology

Presented as the ordered causal chain above. Core molecular processes: nucleotide-excision repair (GO:0006289) and transcription-coupled repair (GO:0006283) failure secondary to disrupted PCNA–partner (FEN1/LIG1) interactions and reduced functional clamp levels; downstream DNA-damage accumulation and post-mitotic neuronal degeneration.

7. Anatomical Structures Affected

Primary: cerebellum (UBERON:0002037) / nervous system; skin (UBERON:0002097); inner ear/cochlea (UBERON:0001844). Secondary/systemic: skeletal growth (short stature); generalized progeroid changes. Cells: cerebellar neurons/Purkinje cells (CL:0000121), fibroblasts (CL:0000057), keratinocytes (CL:0000312). Subcellular: nucleus, replication fork, DNA-damage sites. Lateralization: bilateral/symmetric (cerebellar, cutaneous).

8. Temporal Development

Onset: childhood, insidious/chronic. Course: progressive neurodegeneration and hearing loss; constitutional short stature; chronic lifelong disease. No spontaneous remission; no formally defined "stages" given rarity — natural history is described only from small cohorts.

9. Inheritance and Population

Inheritance: autosomal recessive. Penetrance: presumed high/complete for biallelic carriers (based on limited cases). Expressivity: likely variable across alleles (S228I vs C148S have distinct biophysics). Founder effect: S228I in the Old Order Amish. Consanguinity/endogamy increases risk. Prevalence: not formally estimated — ultra-rare (fewer than ~20 reported individuals worldwide). Carrier frequency: elevated only within the Amish founder population; negligible elsewhere. No sex bias expected for an autosomal-recessive disorder.

10. Diagnostics

Genetic testing is definitive: targeted PCNA sequencing, gene panels for hereditary ataxia / DNA-repair disorders, or WES/WGS. Cellular/functional assays support the diagnosis: reduced UV survival and impaired post-UV RNA-synthesis recovery in patient fibroblasts; reduced chromatin-bound PCNA; temperature-dependent cellular phenotypes. Distinguishing labs: normal alpha-fetoprotein and negative ATM testing separate ATLD from classical ataxia-telangiectasia [PMID: 33426167]. Imaging: brain MRI shows cerebellar atrophy (as in related DNA-repair ataxias). Differential diagnosis: ataxia-telangiectasia (ATM), ATLD1 (MRE11), ataxia with oculomotor apraxia types 1/2, Cockayne syndrome, xeroderma pigmentosum, trichothiodystrophy.

11. Outcome / Prognosis

Chronic, progressive, lifelong. Neurodegeneration and sensory loss drive morbidity and disability; no curative therapy exists. Formal survival/mortality statistics are unavailable given the tiny population. Prognosis is guarded, with progressive functional decline; prognostic biomarkers are not established.

12. Treatment

No disease-modifying therapy exists. Management is supportive and multidisciplinary (NCIT: Supportive Care): physical, occupational, and speech therapy for ataxia; audiology and hearing aids/cochlear support for hearing loss; dermatologic surveillance and rigorous photoprotection for UV sensitivity; growth and endocrine monitoring; genetic counseling. No pharmacotherapy, gene therapy, cell therapy, or RNA-based therapy is approved or in trials for ATLD2. PCNA is being explored as a small-molecule inhibitor target in oncology (not as therapy for ATLD2), and assay development in that space has incidentally characterized ATLD2 disease biology [PMID: 37511614].

13. Prevention

Primary prevention: genetic counseling, carrier screening in at-risk (e.g., Amish founder) populations, and reproductive options including prenatal or preimplantation genetic testing for known familial variants. Secondary: early molecular diagnosis to enable supportive intervention. Tertiary: photoprotection to limit UV-driven cutaneous damage; rehabilitation to preserve function. No vaccine or population public-health measure is applicable.

14. Other Species / Natural Disease

PCNA is deeply and essentially conserved across eukaryotes; orthologs exist in mouse (Pcna), rat, zebrafish, Drosophila, C. elegans, and yeast. The bacterial functional analog is the β-clamp — a structurally distinct protein but a conceptual parallel as a sliding-clamp interaction hub that binds partners through a conserved clamp-binding motif PMID: 38814467. No naturally occurring ATLD2-equivalent disease is documented in companion animals or wildlife (OMIA), reflecting the specificity of the human hypomorphic alleles.

15. Model Organisms

No published animal model specifically recapitulates ATLD2. The principal experimental systems are patient-derived fibroblasts and lymphoblasts (in vitro), which display the UV-sensitivity, reduced chromatin-bound PCNA, and temperature-dependent phenotypes that define the disorder [PMID: 24911150; 36990216]. Recombinant PCNA biochemistry and X-ray crystallography provided the structural mechanism [PMID: 26688547]. Because complete Pcna knockout is embryonic-lethal, any faithful mouse model would need to be a knock-in of the specific hypomorphic allele (S228I or C148S) — a clear and feasible gap for future work.

Evidence Base

PMID Title (abbrev.) Role in this report
24911150 Hypomorphic PCNA mutation underlies a human DNA repair disorder Landmark: defines the disease, identifies S228I, cardinal phenotype, NER defect, FEN1/LIG1 disruption
36990216 A thermosensitive PCNA allele underlies an ataxia-telangiectasia-like disorder Second causal allele C148S; thermolability as unifying mechanism; reduced chromatin-bound PCNA
26688547 A Disease-Causing Variant in PCNA Disrupts a Promiscuous Protein Binding Site Crystal structure of S228I; large conformational change remodels client pocket; client-selective effect
33984330 Unlocking the PIP-box… Establishes PCNA as a >200-partner PIP-box hub — basis for hub fragility
33426167 …How to Identify the Ataxia Telangiectasia-Like Disorders Nosology and diagnostic differentiation from AT (AFP, ATM testing)
37511614 A FRET-Based Assay for the Identification of PCNA Inhibitors Frames ATLD2 as a DNA-repair neurodegenerative disease; PCNA druggability context
23535145 Dissection of cell cycle-dependent dynamics of Dnmt1… PCNA recruits DNMT1 to replication sites — basis for inferred epigenetic branch
17236820 Neurons and astrocytes exhibit lower GG-NER than fibroblasts Explains neuronal vulnerability to repair deficiency
24733832 ATLD clinical case (hypogonadism/hypersegmented neutrophils) Clinical context for the ATLD spectrum
23436002 Italian ATLD siblings, long clinical course Natural-history context (ataxia, oculomotor apraxia)
23622410 Progressive cerebellar atrophy / hereditary ataxias Imaging/DNA-repair ataxia context (cerebellar atrophy)
17994007 Np95 mediates epigenetic inheritance by recruiting Dnmt1 Supports maintenance-methylation machinery context
38814467 β-clamp structure/interactions review Comparative sliding-clamp biology
25972089 p21 exploits Tyr151 as a tether for high-affinity PCNA binding PIP-box affinity/plasticity; why p21 is spared

Evidence-type distribution: Human clinical + patient-cell (in vitro): PMIDs 24911150, 36990216, 33426167, 24733832, 23436002, 23622410. Structural/biochemical (in vitro/computational): 26688547, 33984330, 25972089, 38814467, 37511614. Model-system/mechanistic (in vitro): 23535145, 17994007, 17236820.

Limitations and Knowledge Gaps

  1. Extremely small evidence base. The disease is defined by two alleles and a handful of individuals (predominantly one Amish kindred plus C148S cases). Penetrance, expressivity, prevalence, and natural-history parameters are therefore anecdotal, not statistical.
  2. No animal model. No knock-in mouse or other organism reproduces ATLD2; tissue-specific mechanisms (especially cerebellar tropism) are inferred from patient cells and general neuron-NER biology rather than directly demonstrated in vivo.
  3. Cerebellar selectivity is unexplained at the molecular level. Why the cerebellum is preferentially affected — beyond the general observation that post-mitotic neurons have low NER — is not established for ATLD2 specifically.
  4. The epigenetic branch is inferential. PCNA–DNMT1 coupling is well established biochemically, but altered maintenance methylation has not been measured in ATLD2 patient tissues.
  5. No biomarkers or therapeutics. There are no validated prognostic biomarkers and no disease-modifying treatment; management is entirely supportive.
  6. Allele-specific mechanism heterogeneity. S228I (pocket remodeling) and C148S (thermolability) act through partly different biophysics; whether they produce identical clinical courses is unknown given sample size.

Proposed Follow-up Experiments / Actions

  1. Generate allele-specific knock-in mouse models (Pcna^S228I and Pcna^C148S), including conditional/neuron-restricted alleles, to test cerebellar vulnerability in vivo and produce a preclinical platform.
  2. iPSC-derived cerebellar organoids / Purkinje neurons from patient fibroblasts to model neuron-specific damage accumulation and screen candidate neuroprotective interventions.
  3. Directly measure DNA methylation (whole-genome bisulfite / EM-seq) in patient cells to confirm or refute the inferred DNMT1/epigenetic branch (Finding 8).
  4. Quantitative interactome mapping (BioID or IP-MS of mutant vs WT PCNA on chromatin) to define the full re-weighted partner set beyond FEN1/LIG1 and identify additional impaired repair pathways.
  5. Structural and biophysical characterization of C148S–chromatin dynamics and clamp-loading efficiency to complement the existing S228I crystal structure and test the thermolability model at the loading step.
  6. Establish an international patient registry to capture natural history, penetrance, expressivity, imaging, and audiologic progression — essential given the ultra-rare status.
  7. Explore proteostasis/temperature-buffering strategies for the thermolabile C148S allele and small molecules that stabilize the mutant PCNA fold, as candidate disease-modifying approaches.

Report compiled from an autonomous multi-iteration literature-based investigation. All mechanistic and clinical claims are attributed to the cited primary literature (PMIDs). Inferred steps (cerebellar-tropism specifics, epigenetic branch) are explicitly flagged as not yet demonstrated in ATLD2.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 14
Resolved 14
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 14
On topic 7
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 29
Resolved 27
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 1
Terms whose name was checked 5
Terms named correctly 3
Terms named as a different term 1
Terms whose name is worth a second look 1

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:0014399 (3 mentions) - the report calls it "if available"; MONDO calls it ataxia-telangiectasia-like disorder 2

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:0006266 (obsolete DNA ligation) (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:0000992 (1 mention) - the report calls it "Cutaneous photosensitivity / UV sensitivity"; HP calls it Cutaneous photosensitivity