SQSTM1-related Multisystem Proteinopathy

Mendelian MONDO:0800464 Pathograph 38 Show in embeddings browser Multisystem Proteinopathy Neuromuscular Disorder Neurodegenerative Disorders

SQSTM1-related multisystem proteinopathy (MSP4) is an adult-onset, autosomal dominant disorder caused by heterozygous variants in SQSTM1, which encodes the ubiquitin-binding selective-autophagy receptor and signalling scaffold p62/sequestosome-1. The same gene, and in some families the same allele (most often p.Pro392Leu), produces three clinical presentations with strongly variable penetrance: Paget disease of bone (PDB3), frontotemporal dementia and/or amyotrophic lateral sclerosis (FTDALS3), and a late-onset distal myopathy with rimmed vacuoles (DMRV). They occur alone or together within a family or an individual. The brain, spinal cord and muscle presentations share a pathology of p62- and TDP-43-positive ubiquitinated inclusions, consistent with failed p62-mediated clearance of ubiquitinated cargo. The bone presentation is driven by osteoclast precursors that are hypersensitive to RANKL with enhanced NF-kB signalling, and the extent to which it shares the autophagy lesion of the neuromuscular presentations is not settled. The myopathy is frequently digenic, with the TIA1 p.Asn357Ser variant co-inherited alongside the SQSTM1 variant. This entry covers the dominant, heterozygous disease only. Biallelic loss-of-function SQSTM1 variants cause a different, recessive childhood-onset neurodegeneration with ataxia, dystonia and gaze palsy, curated separately as SQSTM1-Related_Childhood-Onset_Neurodegeneration.

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1
Inheritance
10
Pathophys.
25
Phenotypes
1
Gaps
38
Pathograph
2
Genes
2
Variants
1
Medical Actions
3
Subtypes
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Trials
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References
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Deep Research
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Inheritance

1
Autosomal dominant inheritance HP:0000006
Heterozygous SQSTM1 variants segregate dominantly with disease, but penetrance of each presentation is incomplete and age-dependent, so many carriers present as sporadic cases and relatives with the same variant may show different presentations.
Autosomal dominant inheritance Penetrance: INCOMPLETE
Show evidence (4 references)
PMID:26208961 SUPPORT Human Clinical
"Similar to mutations in VCP, dominantly inherited mutations in SQSTM1 are now associated with rimmed vacuolar myopathy, Paget disease of bone, amyotrophic lateral sclerosis, and frontotemporal dementia."
States dominant inheritance across all four presentations.
PMID:26208961 SUPPORT Human Clinical
"The identification of SQSTM1 mutations in sporadic disease is likely due to its reduced penetrance."
Supports incomplete penetrance.
PMID:17229007 SUPPORT Human Clinical
"Finally, the P392L mutation is transmitted as an autosomal dominant trait in the Quebecois families, with a high but incomplete penetrance peaking after age 60."
Age-dependent, incomplete penetrance of P392L for PDB.
+ 1 more reference
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Subtypes

3
Paget disease of bone 3 (SQSTM1) MONDO:0008176
SQSTM1 hgnc:11280 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SQSTM1 (hgnc:11280). hgnc:11280 is a gene from the HUGO Gene Nomenclature Committee.
Focal, often polyostotic Paget disease of bone caused by heterozygous SQSTM1 variants that cluster in and around the C-terminal ubiquitin-associated (UBA) domain, recurrently p.Pro392Leu. It is the commonest and best-penetrant presentation; carriers are diagnosed earlier and with more affected bones than patients without a variant. Also carried as a subtype row of the Paget_Disease_of_Bone entry.
Show evidence (2 references)
PMID:12374763 SUPPORT Human Clinical
"These studies confirm that mutations affecting the ubiquitin-binding domain of SQSTM1 are a common cause of familial and sporadic Paget's disease of bone."
Mutation screening of familial and sporadic PDB establishes UBA-domain SQSTM1 variants as the cause of this subtype.
PMID:11992264 SUPPORT Human Clinical
"Our data demonstrate that two independent mutational events at the same position in SQSTM1/p62 caused PDB in a high proportion of French Canadian patients."
The original identification of the recurrent P392L allele in PDB families mapped to the PDB3 locus.
Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 MONDO:0014640
SQSTM1 hgnc:11280 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SQSTM1 (hgnc:11280). hgnc:11280 is a gene from the HUGO Gene Nomenclature Committee.
Behavioural-variant frontotemporal dementia, amyotrophic lateral sclerosis, or both, in carriers of heterozygous SQSTM1 variants. ALS/FTD-associated variants are spread across the whole protein, not only the UBA domain, and some (p.Pro392Leu, p.Pro387Leu, p.Ala381Val) are shared with PDB. Many patients are sporadic, which is attributed to reduced penetrance.
Show evidence (3 references)
PMID:22084127 SUPPORT Human Clinical
"We identified 10 novel SQSTM1 mutations (9 heterozygous missense and 1 deletion) in 15 patients (6 with familial ALS and 9 with sporadic ALS)."
First case-control screen linking heterozygous SQSTM1 variants to familial and sporadic ALS.
PMID:24042580 SUPPORT Human Clinical
"To our knowledge, this is the first study that clearly demonstrates a segregation of a SQSTM1 mutation with dementia in 2 families, F297 and FR1324."
Family segregation of SQSTM1 variants with frontotemporal dementia.
PMID:22972638 SUPPORT Human Clinical
"We identified 6 missense mutations in the coding region of SQSTM1 in patients with either FTLD or ALS, none of which were found in healthy controls or patients with PDB."
Independent cohort showing SQSTM1 missense variants in FTLD and ALS.
Distal myopathy with rimmed vacuoles (SQSTM1) MONDO:0014945
SQSTM1 hgnc:11280 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SQSTM1 (hgnc:11280). hgnc:11280 is a gene from the HUGO Gene Nomenclature Committee. TIA1 hgnc:11802 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in TIA1 (hgnc:11802). hgnc:11802 is a gene from the HUGO Gene Nomenclature Committee. Digenic inheritance
Late-onset, often asymmetric distal myopathy with ankle dorsiflexion and finger extensor weakness, mildly raised creatine kinase and rimmed vacuoles containing p62 and TDP-43. First described with the SQSTM1 c.1165+1G>A splice variant, which can cause myopathy without bone or brain involvement. Most subsequently reported patients also carry TIA1 p.Asn357Ser, and the myopathy is then considered digenic. A frameshift variant has also been reported with a proximal, limb-girdle myopathy with rimmed vacuoles.
Show evidence (4 references)
PMID:26208961 SUPPORT Human Clinical
"Affected patients had late-onset distal lower extremity weakness, myopathic features on EMG, and muscle pathology demonstrating rimmed vacuoles with both TAR DNA-binding protein 43 and SQSTM1 inclusions."
The founding description of SQSTM1 distal myopathy with rimmed vacuoles.
PMID:26208961 SUPPORT Human Clinical
"Notably, the patients described in this study did not have evidence of PDB, ALS, or FTD, suggesting that myopathy can occur in isolation with c.1165+1 G>A SQSTM1 variant."
Shows the myopathy can be the sole manifestation.
PMID:36998782 SUPPORT Human Clinical
"Herein, we report a new phenotype of SQSTM1-associated proteinopathy, a novel frameshift mutation in SQSTM1 causing proximal MRV."
Extends the muscle presentation to proximal weakness.
+ 1 more reference
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Discussions and Knowledge Gaps

1
Does the bone presentation share the autophagy lesion of the neurological and muscle presentations, and what decides which presentation a given SQSTM1 carrier develops?
KNOWLEDGE GAP bone_versus_neuromuscular_arm
Attached to
pathophysiology#Enhanced RANKL-NF-kB Signalling in Osteoclast Precursors pathophysiology#Impaired p62-Mediated Selective Autophagy
The entry models one shared variant node with two branches: a UBA-domain/NF-kB branch for bone and a cargo-receptor/autophagy branch for neurons and muscle. The branches are not cleanly separable, since mutant osteoclast lineage cells also show autophagy marker changes, and the same allele (p.Pro392Leu) produces either or both. Even within bone, two knock-in mouse lines disagree on whether the variant alone produces lesions or needs a second factor such as measles virus nucleocapsid protein; the Paget_Disease_of_Bone entry discusses that viral hypothesis, which studies of human pagetic bone have largely failed to confirm. Co-inherited variants are a partial answer for muscle (TIA1 p.Asn357Ser) and possibly for brain (a C9orf72 expansion was found with an SQSTM1 variant in one FTD case), but no determinant of the bone versus brain split is known. Coexistence of PDB with ALS/FTD may also be under-ascertained, because FTD families were not examined for bone disease and PDB families were not assessed for dementia.
Show evidence (2 references)
PMID:27554286 SUPPORT BACKGROUND Human Clinical
"Coexistence of PDB and ALS-FTLD is apparently rare and precisely how different SQSTM1 mutations (some of which are common to both disorders) can lead to either neurodegeneration or PDB is currently unknown"
States the open question directly.
PMID:26208961 SUPPORT Human Clinical
"Why some patients develop PDB or ALS and others develop a myopathy is unclear, but it may be related to the presence of other inherited genetic modifiers."
Proposes genetic modifiers as the source of pleiotropy.
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Pathophysiology

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Heterozygous SQSTM1 Variant Alters p62 Domains
Mechanism confidence: Established
p62 is a multidomain scaffold: an N-terminal PB1 oligomerisation domain, a TRAF6-binding region, an LC3-interacting region (LIR) that docks it to the forming autophagosome, a KEAP1-interacting region (KIR), and a C-terminal UBA domain that binds ubiquitinated cargo. PDB-associated variants cluster in and around the UBA domain, whereas ALS/FTD-associated variants are distributed across the protein, including the LIR and KIR. Several alleles, p.Pro392Leu above all, occur in both groups. Which presentation an allele produces is therefore only partly predicted by where it lies.
SQSTM1 hgnc:11280 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SQSTM1 (hgnc:11280). hgnc:11280 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context SQSTM1 hgnc:11280 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns SQSTM1 (hgnc:11280). hgnc:11280 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HETEROZYGOUS
Downstream
Impaired p62-Mediated Selective Autophagy Variants in the UBA domain and LIR reduce binding of ubiquitinated cargo or of LC3, weakening p62's cargo-receptor function.
Impaired KEAP1-NRF2 Antioxidant Response Variants in or near the KIR reduce KEAP1 binding and NRF2 activation.
Enhanced RANKL-NF-kB Signalling in Osteoclast Precursors UBA-domain variants lose ubiquitin binding and increase NF-kB activation downstream of RANK in osteoclast precursors.
Show evidence (4 references)
PMID:27554286 SUPPORT BACKGROUND Human Clinical
"SQSTM1 encodes the SQSTM1/p62 protein and the overwhelming majority of mutations associated with PDB cluster within and around the C-terminal ubiquitin-associated (UBA) domain, whereas mutations associated with ALS-FTLD occur more widely throughout the protein sequence"
Introduction of a functional study summarising the domain distribution of bone-associated and neurodegeneration-associated variants.
PMID:17229007 SUPPORT Human Clinical
"The 14 mutations reported in SQSTM1/p62 all affect the ubiquitin-associated domain of the protein."
The PDB-associated alleles known at the time all lie in the UBA domain.
PMID:24486447 SUPPORT Other
"Although several SQSTM1 mutations are common to both ALS/FTLD and PDB, many are ALS/FTLD-specific."
Review stating that some alleles are shared between the bone and neurodegenerative presentations and others are not.
+ 1 more reference
Impaired p62-Mediated Selective Autophagy
Mechanism confidence: Established
p62 links ubiquitinated proteins to LC3 on the forming autophagosome so they can be degraded. Disease variants reduce LC3B recognition (LIR variants such as p.Leu341Val), reduce TBK1/ULK1-dependent phosphorylation of the UBA domain that activates cargo binding, or remove the UBA domain (the c.1165+1G>A splice product). The shared result is slower autophagic clearance of ubiquitinated proteins, the lesion the neurodegenerative and myopathic presentations are thought to share with VCP-, OPTN- and TBK1-related disease.
SQSTM1 hgnc:11280 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SQSTM1 (hgnc:11280). hgnc:11280 is a gene from the HUGO Gene Nomenclature Committee.
aggrephagy GO:0035973 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased aggrephagy (GO:0035973). GO:0035973 is a biological process from the Gene Ontology. autophagy GO:0006914 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased autophagy (GO:0006914). GO:0006914 is a biological process from the Gene Ontology.
autophagy cargo adaptor activity GO:0160247 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased autophagy cargo adaptor activity (GO:0160247). GO:0160247 is a molecular function from the Gene Ontology. ubiquitin binding GO:0043130 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased ubiquitin binding (GO:0043130). GO:0043130 is a molecular function from the Gene Ontology.
Downstream
p62- and TDP-43-Positive Ubiquitinated Inclusions Uncleared ubiquitinated proteins accumulate with p62 and TDP-43 in neurons and myofibres.
Persistent Stress Granules p62 participates in stress granule clearance; mutant or depleted p62 slows it.
Show evidence (4 references)
PMID:26208961 SUPPORT BACKGROUND Other
"SQSTM1 is an autophagic adaptor that shuttles aggregated and ubiquitinated proteins to the autophagosome for degradation via its C-terminal UBA domain."
States the normal cargo-receptor function that disease variants impair.
PMID:27158844 SUPPORT In Vitro
"Here we show that although representing a conservative substitution and predicted to be benign, the ALS-associated L341V mutation of SQSTM1 is defective in recognition of LC3B."
An ALS-associated LIR variant directly impairs docking of p62 to LC3B.
PMID:27158844 SUPPORT In Vitro
"Our data supports a model in which the L341V mutation limits the critical step of SQSTM1 recruitment to the phagophore."
Functional consequence of the LIR variant in motor neuron-like cells.
+ 1 more reference
Impaired KEAP1-NRF2 Antioxidant Response
Mechanism confidence: Provisional
p62 binds KEAP1 through its KIR and so releases NRF2 to activate antioxidant genes. ALS/FTD variants in or next to the KIR (p.Pro348Leu, p.Gly351Ala, p.Gly427Arg through loss of Ser351 phosphorylation) reduce KEAP1 binding and NRF2 target-gene expression, and p.Gly427Arg increases TDP-43-associated stress granule formation under oxidative stress. Shown in cell models for a subset of neurodegeneration-associated alleles only.
SQSTM1 hgnc:11280 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SQSTM1 (hgnc:11280). hgnc:11280 is a gene from the HUGO Gene Nomenclature Committee.
cellular response to oxidative stress GO:0034599 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cellular response to oxidative stress (GO:0034599). GO:0034599 is a biological process from the Gene Ontology.
Downstream
Persistent Stress Granules Under oxidative stress the G427R variant increases TDP-43-associated stress granule formation.
Show evidence (2 references)
PMID:27554286 SUPPORT In Vitro
"Consistent with impaired Keap1 binding, the P348L and G351A KIR mutants showed reduced ability to activate Nrf2 signalling compared to wild-type SQSTM1/p62 in antioxidant response element (ARE)-luciferase reporter assays."
KIR variants found in ALS/FTD reduce NRF2 activation in reporter assays.
PMID:31362587 SUPPORT In Vitro
"Moreover, disease mutation SQSTM1G427R abolishes phosphorylation of Ser351 and impairs KEAP1-SQSTM1 interaction, thus diminishing NFE2L2/Nrf2-targeted gene expression and increasing TARDBP/TDP-43 associated stress granule formation under oxidative stress."
A UBA-domain ALS/FTD variant disrupts KEAP1 binding and NRF2 signalling.
Persistent Stress Granules
Mechanism confidence: Provisional
Stress granules are transient ribonucleoprotein condensates that must be disassembled, partly by autophagy, once stress resolves. Mutant or depleted p62 slows their clearance. The TIA1 p.Asn357Ser variant enhances TIA1 phase separation, and granules made with it persist, bind more p62 and accumulate ubiquitinated and aggregated proteins. Co-expression of mutant TIA1 and mutant SQSTM1 in myoblasts is synergistically toxic, which is the proposed basis of the digenic myopathy.
SQSTM1 hgnc:11280 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SQSTM1 (hgnc:11280). hgnc:11280 is a gene from the HUGO Gene Nomenclature Committee. TIA1 hgnc:11802 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TIA1 (hgnc:11802). hgnc:11802 is a gene from the HUGO Gene Nomenclature Committee.
cytoplasmic stress granule disassembly GO:0035617 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cytoplasmic stress granule disassembly (GO:0035617). GO:0035617 is a biological process from the Gene Ontology.
Downstream
p62- and TDP-43-Positive Ubiquitinated Inclusions Persistent granules accumulate ubiquitin conjugates and aggregated proteins.
Rimmed Vacuolar Myofibre Degeneration Impaired stress granule clearance with mutant TIA1 and SQSTM1 is toxic to myoblasts.
Show evidence (3 references)
PMID:29457785 SUPPORT In Vitro
"Depletion of SQSTM1 or the introduction of a mutant version of SQSTM1 similarly impairs SG dynamics."
Mutant SQSTM1 impairs stress granule dynamics in cells.
PMID:29457785 SUPPORT In Vitro
"Synergistic expression of the TIA1-N357S variant and a SQSTM1-A390X mutation in myoblasts leads to impaired SG clearance and myotoxicity relative to control myoblasts."
Combined TIA1 and SQSTM1 variants impair stress granule clearance and are toxic to muscle cells.
PMID:33145792 SUPPORT Other
"all of which share disruption of RNA stress granule function and autophagic degradation."
Review placing stress granule and autophagy defects at the centre of the multisystem proteinopathies including SQSTM1.
p62- and TDP-43-Positive Ubiquitinated Inclusions
Mechanism confidence: Established
The unifying pathology of the neurological and muscle presentations: ubiquitinated inclusions containing p62 and TDP-43 in motor neurons, in frontal cortex neurons and glia (FTLD-TDP), and in vacuolated myofibres. The aggregate species substituted here for the module's generic misfolded protein are p62 itself and TDP-43.
motor neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves motor neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology. cerebral cortex neuron CL:0010012 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cerebral cortex neuron (CL:0010012). CL:0010012 is a cell type from the Cell Ontology. skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
p62 and TDP-43 inclusion GO:0016234 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves p62 and TDP-43 inclusion, annotated with inclusion body (GO:0016234). GO:0016234 is a cellular component from the Gene Ontology.
Downstream
Upper and Lower Motor Neuron Degeneration
Frontotemporal Cortical Neurodegeneration
Rimmed Vacuolar Myofibre Degeneration
Show evidence (4 references)
PMID:23417734 SUPPORT Human Clinical
"Neuropathology analysis of three patients carrying SQSTM1 variants revealed the presence of large round p62 inclusions in motor neurons, and immunoblot analysis showed an increased p62 and TDP-43 protein levels in the spinal cord."
Autopsy evidence of p62 inclusions and TDP-43 accumulation in SQSTM1 ALS.
PMID:26234378 SUPPORT Human Clinical
"The present study supports previous observations on amyotrophic lateral sclerosis (ALS) that SQSTM1 mutations consistently associate with TDP-43 pathology."
Clinicopathological FTD cases with SQSTM1 variants show TDP-43 pathology.
PMID:26208961 SUPPORT Human Clinical
"The disparate phenotypes in muscle, brain, spinal cord, and bone are unified by the pathologic accumulation of ubiquitin and TDP-43."
Places the shared ubiquitin and TDP-43 pathology across tissues.
+ 1 more reference
Upper and Lower Motor Neuron Degeneration
Mechanism confidence: Established
Degeneration of upper and lower motor neurons with p62 and TDP-43 inclusions in spinal motor neurons, producing ALS alone or combined with frontotemporal dementia.
motor neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves motor neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology.
Downstream
Amyotrophic lateral sclerosis
Fasciculations
Dysarthria
Show evidence (2 references)
PMID:22084127 SUPPORT Human Clinical
"Our findings provide evidence of a direct genetic role for p62 in ALS pathogenesis"
Links SQSTM1 variants to motor neuron disease.
PMID:23417734 SUPPORT Human Clinical
"Neuropathology analysis of three patients carrying SQSTM1 variants revealed the presence of large round p62 inclusions in motor neurons, and immunoblot analysis showed an increased p62 and TDP-43 protein levels in the spinal cord."
Motor neurons are the site of p62 inclusion pathology in SQSTM1 ALS.
Frontotemporal Cortical Neurodegeneration
Mechanism confidence: Established
Frontal and temporal lobar degeneration with TDP-43 pathology (type B in the best-characterised case, with oligodendroglial inclusions), seen on imaging as bilateral frontal or perisylvian atrophy with frontotemporal hypoperfusion.
cerebral cortex neuron CL:0010012 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cerebral cortex neuron (CL:0010012). CL:0010012 is a cell type from the Cell Ontology.
Downstream
Frontotemporal dementia
Disinhibition
Apathy
Impaired executive functioning
Polyphagia
Parkinsonism
Cognitive impairment
Show evidence (2 references)
PMID:26234378 SUPPORT Human Clinical
"TDP-43 pathology was consistent with the features of type B of FTLD-TDP pathology."
Neuropathology of an SQSTM1 p.Glu396* carrier with behavioural FTD.
PMID:24042580 SUPPORT Human Clinical
"Notably, brain imaging revealed bilateral frontal or predominantly perisylvian atrophy, which was associated with callosal and periventricular T2-weighted white matter hypersignals that were moderate but present in all the cases."
Imaging shows frontotemporal atrophy in SQSTM1 FTD families.
Rimmed Vacuolar Myofibre Degeneration
Mechanism confidence: Established
Myopathic degeneration of distal limb muscles with rimmed vacuoles, myofibrillar disorganisation, Z-band streaming and fibres containing p62, TDP-43 and LC3. With the c.1165+1G>A splice variant, a UBA-truncated and a PEST2-deleted p62 are made; the PEST2-deleted form builds large sarcoplasmic inclusions in muscle.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
skeletal muscle tissue UBERON:0001134 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skeletal muscle tissue (UBERON:0001134). UBERON:0001134 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Distal muscle weakness
Foot dorsiflexor weakness
Weakness of long finger extensor muscles
Scapular winging
Rimmed vacuoles
Z-band streaming
Elevated circulating creatine kinase
Myopathic EMG
Show evidence (2 references)
PMID:26208961 SUPPORT Human Clinical
"Affected patients had late-onset distal lower extremity weakness, myopathic features on EMG, and muscle pathology demonstrating rimmed vacuoles with both TAR DNA-binding protein 43 and SQSTM1 inclusions."
Muscle pathology of the SQSTM1 myopathy.
PMID:26208961 SUPPORT Human Clinical
"Electron microscopy (EM) demonstrated large foci of myofibrillar disorganization and Z-band streaming (figure 2, G and H)."
Ultrastructural myofibrillar damage in a patient biopsy.
Enhanced RANKL-NF-kB Signalling in Osteoclast Precursors
Mechanism confidence: Established
UBA-domain variants impair p62 ubiquitin binding and raise basal and RANKL-induced NF-kB activation in osteoclast precursors, which become hypersensitive to RANKL and form larger osteoclasts with more nuclei that resorb more bone. The degree of NF-kB activation by a given UBA variant tracks the number of affected bones in patients. Osteoclast precursors from knock-in mice also show markers of dysregulated autophagy, so this arm is not purely a signalling defect.
osteoclast CL:0000092 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoclast (CL:0000092). CL:0000092 is a cell type from the Cell Ontology.
SQSTM1 hgnc:11280 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SQSTM1 (hgnc:11280). hgnc:11280 is a gene from the HUGO Gene Nomenclature Committee.
positive regulation of canonical NF-kappaB signal transduction GO:0043123 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of canonical NF-kappaB signal transduction (GO:0043123). GO:0043123 is a biological process from the Gene Ontology. positive regulation of osteoclast differentiation GO:0045672 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of osteoclast differentiation (GO:0045672). GO:0045672 is a biological process from the Gene Ontology.
ubiquitin binding GO:0043130 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased ubiquitin binding (GO:0043130). GO:0043130 is a molecular function from the Gene Ontology.
Downstream
Focal Accelerated Bone Turnover
Show evidence (5 references)
PMID:24642144 SUPPORT In Vitro
"Both impaired SQSTM1's ubiquitin-binding function in pull-down assays and resulted in activation of basal NF-κB signalling, compared to wild-type, in reporter assays."
Two PDB UBA-domain variants lose ubiquitin binding and activate NF-kB.
PMID:24642144 SUPPORT Human Clinical
"We found evidence for a relationship between the ability of different UBA domain mutants to activate NF-κB signalling in vitro and number of affected sites in vivo in 1152 PDB patients from the UK and Italy"
NF-kB activation by an allele relates to disease extent in patients.
PMID:16813535 SUPPORT In Vitro
"p62 mutants increased NF-kappaB activation and significantly potentiated osteoclast formation and bone resorption in human primary cell cultures."
Mutant p62 enhances NF-kB activation and osteoclastogenesis in human cells.
+ 2 more references
Focal Accelerated Bone Turnover
Mechanism confidence: Established
Focal lesions with increased resorption and disorganised formation of woven bone, the pagetic lesion. Whether the germline UBA variant is sufficient on its own is contested: one P394L knock-in mouse line developed focal pagetic lesions without any other trigger, while an independently made P394L knock-in line had more osteoclasts but no lesions unless measles virus nucleocapsid protein was also expressed in osteoclasts.
multinuclear osteoclast CL:0000779 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves multinuclear osteoclast (CL:0000779). CL:0000779 is a cell type from the Cell Ontology.
Downstream
Paget disease of bone
Elevated circulating alkaline phosphatase
Bone pain
Bone deformity
Hearing impairment Pagetic involvement of the skull, including the temporal bone, is the usual route to hearing loss in Paget disease of bone.
Osteosarcoma
Show evidence (5 references)
PMID:21515589 SUPPORT Model Organism
"Lesions predominantly affected the lower limbs in an asymmetric manner and were characterized by focal increases in bone turnover, with increased bone resorption and formation, disruption of the normal bone architecture and accumulation of woven bone."
The pagetic lesion reproduced in knock-in mice.
PMID:21515589 SUPPORT Model Organism
"These studies demonstrate that SQSTM1 mutations can cause a PDB-like skeletal disorder in the absence of an additional trigger"
The UBA variant is sufficient for the bone lesion in mice.
PMID:16877352 SUPPORT In Vitro
"Overexpression of p62DeltaUBA potentiated the formation of abnormally large multinucleated osteoclasts and resorption of bone, reminiscent of PDB."
Loss of the UBA domain produces pagetic-like osteoclasts in culture.
+ 2 more references
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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 SQSTM1-related Multisystem Proteinopathy 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

25
Ear 1
Hearing impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38123339 SUPPORT BACKGROUND Human Clinical
"These abnormalities can cause various complications including bone pain, deformity, pathological fractures, nerve compression syndromes, deafness, secondary osteoarthritis and osteosarcoma"
The ZiPP report's introduction lists deafness among the complications of Paget disease of bone.
Limbs 3
Foot dorsiflexor weakness HP:0009027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ankle dorsiflexion weakness, annotated with Foot dorsiflexor weakness (HP:0009027). HP:0009027 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26208961 SUPPORT Human Clinical
"developed right ankle dorsiflexion weakness at age 52"
Ankle dorsiflexion weakness as the presenting sign in the index family.
Weakness of long finger extensor muscles FREQUENT HP:0009077 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Finger extensor weakness, annotated with Weakness of long finger extensor muscles (HP:0009077). HP:0009077 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39142003 SUPPORT Human Clinical
"mainly asymmetric, distal ankle and hand finger extension weakness (75%)"
Finger extension weakness in three quarters of digenic myopathy patients.
Scapular winging HP:0003691 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scapular winging (HP:0003691). HP:0003691 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26208961 SUPPORT Human Clinical
"mild shoulder abduction weakness (left greater than right), bilateral scapular winging"
Scapular winging in the proband of the index family.
Metabolism 2
Elevated circulating alkaline phosphatase Elevated circulating alkaline phosphatase concentration HP:0003155 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated serum alkaline phosphatase, annotated with Elevated circulating alkaline phosphatase concentration (HP:0003155). HP:0003155 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32176830 SUPPORT Human Clinical
"Serum concentrations of total alkaline phosphatase (ALP) normalized to the upper limit of normal in each center were higher in those with lesions"
ALP is raised in SQSTM1 carriers with PDB lesions.
Elevated circulating creatine kinase VERY_FREQUENT Elevated circulating creatine kinase activity HP:0003236 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mildly elevated creatine kinase, annotated with Elevated circulating creatine kinase activity (HP:0003236). HP:0003236 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39142003 SUPPORT Human Clinical
"mild CK elevation (82.4%) and myopathic EMG"
Mild CK elevation in most digenic myopathy patients.
Musculoskeletal 8
Bone deformity Abnormal skeletal morphology HP:0011842 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bone deformity, annotated with Abnormal skeletal morphology (HP:0011842). HP:0011842 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (1 reference)
PMID:38123339 SUPPORT BACKGROUND Human Clinical
"These abnormalities can cause various complications including bone pain, deformity, pathological fractures, nerve compression syndromes, deafness, secondary osteoarthritis and osteosarcoma"
The ZiPP report's introduction lists deformity among the complications of Paget disease of bone.
Osteosarcoma HP:0002669 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteosarcoma (HP:0002669). HP:0002669 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38123339 SUPPORT BACKGROUND Human Clinical
"These abnormalities can cause various complications including bone pain, deformity, pathological fractures, nerve compression syndromes, deafness, secondary osteoarthritis and osteosarcoma"
The ZiPP report's introduction lists osteosarcoma among the complications of Paget disease of bone.
Paget disease of bone HP:0034159 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Paget disease of bone (HP:0034159). HP:0034159 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:12374763 SUPPORT Human Clinical
"The most common mutation was the P392L change in exon 8, which was found in 13 of 68 families (19.1%)."
PDB families carrying the recurrent SQSTM1 variant.
PMID:20499339 SUPPORT Human Clinical
"Mutation carriers had an earlier age at diagnosis (59.4 ± 11.5 versus 65.0 ± 10.4 years, p < .0001) and a greater number of affected bones (3.2 ± 1.2 versus 2.1 ± 1.2, p < .001)"
SQSTM1-related PDB is earlier and more extensive.
Increased susceptibility to fractures HP:0002659 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased susceptibility to fractures (HP:0002659). HP:0002659 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20499339 SUPPORT Human Clinical
"During the study, fractures were more common in carriers (12.5% versus 5.3%, p = .011), although most of these occurred in unaffected bone."
Higher fracture rate in SQSTM1 carriers with PDB.
Distal muscle weakness HP:0002460 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal muscle weakness (HP:0002460). HP:0002460 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26208961 SUPPORT Human Clinical
"Affected patients had late-onset distal lower extremity weakness, myopathic features on EMG, and muscle pathology demonstrating rimmed vacuoles with both TAR DNA-binding protein 43 and SQSTM1 inclusions."
Distal lower limb weakness in SQSTM1 myopathy.
Myopathic EMG EMG: myopathic abnormalities HP:0003458 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopathic EMG, annotated with EMG: myopathic abnormalities (HP:0003458). HP:0003458 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39142003 SUPPORT Human Clinical
"mild CK elevation (82.4%) and myopathic EMG"
Myopathic EMG in the digenic myopathy series.
Rimmed vacuoles VERY_FREQUENT HP:0003805 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rimmed vacuoles (HP:0003805). HP:0003805 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39142003 SUPPORT Human Clinical
"Muscle biopsy showed rimmed vacuoles (44.4%), myofibrillar disorganization (16.7%) or both (38.9%), with P62/TDP43 aggregates."
Frequency of rimmed vacuoles on muscle biopsy.
Z-band streaming HP:0020203 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Z-band streaming (HP:0020203). HP:0020203 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26208961 SUPPORT Human Clinical
"Electron microscopy (EM) demonstrated large foci of myofibrillar disorganization and Z-band streaming (figure 2, G and H)."
Z-band streaming on electron microscopy of patient muscle.
Nervous System 10
Frontotemporal dementia HP:0002145 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Frontotemporal dementia (HP:0002145). HP:0002145 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24042580 SUPPORT Human Clinical
"Clinically, all the families were affected by bvFTD,19 which was associated with ALS in family F480 (8% of the patients) and with PDB in family FR1324 (30% of the patients)."
Behavioural FTD in all four SQSTM1 families, variably with ALS or PDB.
Disinhibition HP:0000734 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Disinhibition (HP:0000734). HP:0000734 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24042580 SUPPORT Human Clinical
"He developed disinhibition, rituals, verbal stereotypies, indifference, social avoidance, apathy, and reduced verbal fluency but no ALS symptoms."
Disinhibition in an SQSTM1 p.Ala381Val carrier with behavioural FTD.
Apathy HP:0000741 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Apathy (HP:0000741). HP:0000741 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24042580 SUPPORT Human Clinical
"He developed disinhibition, rituals, verbal stereotypies, indifference, social avoidance, apathy, and reduced verbal fluency but no ALS symptoms."
Apathy in an SQSTM1 carrier with behavioural FTD.
Polyphagia HP:0002591 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bulimia, annotated with Polyphagia (HP:0002591). HP:0002591 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24042580 SUPPORT Human Clinical
"initially presented with indifference, disinhibited behavior, and bulimia"
Presenting behavioural features of the index patient of family F297.
Impaired executive functioning HP:0033051 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Executive dysfunction, annotated with Impaired executive functioning (HP:0033051). HP:0033051 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24042580 SUPPORT Human Clinical
"Neuropsychological testing revealed executive dysfunction (Table 2)."
Executive dysfunction on testing in SQSTM1 FTD patients.
Parkinsonism HP:0001300 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Parkinsonism (HP:0001300). HP:0001300 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24042580 SUPPORT Human Clinical
"a limitation of voluntary downward gaze, and she developed extrapyramidal signs."
Extrapyramidal signs in the F297 index patient.
Cognitive impairment OCCASIONAL HP:0100543 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cognitive impairment (HP:0100543). HP:0100543 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39122262 SUPPORT Human Clinical
"Notably, 26% (5/19) of the patients with ALS with SQSTM1 variant in our cohort had comorbid cognitive impairment and 43% (3/7) of them had behavioural variant frontotemporal dementia (FTD)."
Frequency of cognitive impairment in SQSTM1-related ALS.
Amyotrophic lateral sclerosis HP:0007354 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Amyotrophic lateral sclerosis (HP:0007354). HP:0007354 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22084127 SUPPORT Human Clinical
"We identified 10 novel SQSTM1 mutations (9 heterozygous missense and 1 deletion) in 15 patients (6 with familial ALS and 9 with sporadic ALS)."
ALS in SQSTM1 variant carriers.
PMID:39122262 SUPPORT Human Clinical
"Our meta-analysis found a total frequency of SQSTM1 variants in 7183 patients with ALS was 2.4%"
Frequency of SQSTM1 variants among ALS patients.
Fasciculations HP:0002380 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fasciculations (HP:0002380). HP:0002380 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24042580 SUPPORT Human Clinical
"He also had diffuse enhanced reflexes, a right-sided Babinski sign, a bilateral motor deficit, fasciculations, and amyotrophy predominantly affecting the upper limbs."
Upper and lower motor neuron signs in the FTD-ALS proband of family F480.
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:24042580 SUPPORT Human Clinical
"he was examined and was revealed to have dysarthria and dysphonia with stuttering and buccofacial apraxia"
Bulbar involvement in the FTD-ALS proband.
Constitutional 1
Bone pain HP:0002653 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bone pain (HP:0002653). HP:0002653 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38123339 SUPPORT BACKGROUND Human Clinical
"These abnormalities can cause various complications including bone pain, deformity, pathological fractures, nerve compression syndromes, deafness, secondary osteoarthritis and osteosarcoma"
The ZiPP report's introduction lists bone pain among the complications of Paget disease of bone.
🧬

Genetic Associations

2
SQSTM1
Gene: SQSTM1 hgnc:11280 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SQSTM1 (hgnc:11280). hgnc:11280 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE
Show evidence (4 references)
PMID:26208961 SUPPORT Human Clinical
"We have now demonstrated that SQSTM1 can cause a rimmed vacuolar myopathy in addition to ALS, FTD, and PDB and could thus be considered a multisystem proteinopathy or MSP4."
Establishes SQSTM1 as a multisystem proteinopathy gene.
PMID:29457785 SUPPORT Human Clinical
"identical mutations in the autophagic adaptor SQSTM1 can cause varied penetrance of 4 distinct phenotypes"
The same SQSTM1 alleles underlie all four presentations.
PMID:21515589 SUPPORT Model Organism
"These studies demonstrate that SQSTM1 mutations can cause a PDB-like skeletal disorder in the absence of an additional trigger"
In this knock-in line a single allele was sufficient for the bone presentation; an independent line was not (see Focal Accelerated Bone Turnover).
+ 1 more reference
Variants (2)
p.Pro392Leu
Recurrent UBA-flanking missense variant; the most frequent SQSTM1 allele in PDB, also found in FTD, ALS and the digenic myopathy.
Show evidence (2 references)
PMID:11992264 SUPPORT Human Clinical
"led to the identification of a recurrent nonconservative change (P392L) flanking the ubiquitin-associated domain (UBA) (position 394-440) of the protein that was not present in 291 control individuals."
Identification of the recurrent PDB allele.
PMID:23942205 SUPPORT Human Clinical
"The occurrence of the same mutation in ALS and PDB is indicative of a common pathogenic pathway that converges on protein homeostasis."
The same allele in ALS and PDB.
c.1165+1G>A
Splice-donor variant in intron 7 producing UBA-truncated and PEST2-deleted p62; reported in PDB, ALS with PDB, and distal myopathy.
Show evidence (1 reference)
PMID:26208961 SUPPORT Human Clinical
"Sequencing identified a likely pathogenic c.1165+1 G>A splice donor variant in SQSTM1 in the affected members of 1 family and in an unrelated patient with sporadic distal myopathy."
The splice variant in SQSTM1 distal myopathy.
TIA1
Gene: TIA1 hgnc:11802 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TIA1 (hgnc:11802). hgnc:11802 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER
Show evidence (2 references)
PMID:29457785 SUPPORT Human Clinical
"Here, we provide evidence that a TIA1 (p.N357S) variant dictates a myodegenerative phenotype when inherited, along with a pathogenic SQSTM1 mutation."
TIA1 p.N357S as the determinant of the myopathic presentation.
PMID:39142003 SUPPORT Human Clinical
"We confirm an increased burden of the TIA1 p.Asn357Ser variant in distal myopathy patients which could act as a genetic modifier."
Supports the modifier role.
💊

Medical Actions

1
Zoledronic acid
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: zoledronic acid CHEBI:46557 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses zoledronic acid (CHEBI:46557). CHEBI:46557 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
A single 5 mg infusion of zoledronic acid in SQSTM1 carriers identified by family screening was well tolerated, reduced bone turnover markers and prevented progression of early pagetic lesions in a randomised placebo-controlled trial (ZiPP); it was underpowered to show prevention of new lesions. No disease-modifying treatment exists for the neurological or muscle presentations.
Mechanism Target:
Focal Accelerated Bone Turnover — Bisphosphonate inhibition of osteoclastic bone resorption.
Show evidence (2 references)
PMID:38123339 SUPPORT Human Clinical
"Eight of the placebo group had a poor outcome (lesions which were new, unchanged or progressing) compared with none of the ZA group (OR 0.08, 95% CI 0.00 to 0.42, p=0.003)."
Randomised trial result in SQSTM1 carriers.
PMID:38123339 SUPPORT Human Clinical
"Genetic testing for pathogenic SQSTM1 variants coupled with intervention with ZA is well tolerated and has favourable effects on the progression of early PDB."
Trial conclusion supporting genetic testing with targeted zoledronic acid.
🔬

Diagnosis

3
SQSTM1 molecular genetic testing
Sequencing of SQSTM1 confirms the diagnosis. In distal myopathy, TIA1 should be tested together with SQSTM1, because most patients carry both variants.
Genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:38016875 SUPPORT Human Clinical
"Clinical suspicion is necessary to seek both variants."
Recommends testing for both the TIA1 and SQSTM1 variants.
Radionuclide bone scan in carriers
In SQSTM1 carriers, a radionuclide bone scan detects early, asymptomatic pagetic lesions; serum alkaline phosphatase is raised in those with lesions but misses many. Screening for PDB is recommended in SQSTM1 carriers with any presentation.
Bone scan NCIT:C17646 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:32176830 SUPPORT Human Clinical
"Asymptomatic PDB is present in about 9% of SQSTM1 mutation carriers by the fifth decade."
Bone-scan screening of carriers detects asymptomatic lesions.
PMID:32176830 SUPPORT Human Clinical
"the sensitivity of ALP and other markers in detecting lesions was poor"
Biochemical markers alone are insufficient for screening.
PMID:36861178 SUPPORT Human Clinical
"Based on current literature, screening for PDB should be performed in patients with VCP, HNRNPA2B1, HNRNPA1, and SQSTM1 mutations"
Recommends PDB screening in SQSTM1 carriers.
Muscle biopsy
Shows a myopathy with rimmed vacuoles, myofibrillar disorganisation and p62/TDP-43 aggregates.
Muscle biopsy NCIT:C51895 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:39142003 SUPPORT Human Clinical
"Muscle biopsy showed rimmed vacuoles (44.4%), myofibrillar disorganization (16.7%) or both (38.9%), with P62/TDP43 aggregates."
Biopsy findings in the myopathy.
📈

Progression

2
Adult-onset presentation
All three presentations begin in adulthood. In SQSTM1 carriers screened from PDB families, asymptomatic pagetic lesions are already present in about 9% by the fifth decade; dementia and myopathy typically begin in the sixth decade or later.
Show evidence (2 references)
PMID:32176830 SUPPORT Human Clinical
"Asymptomatic PDB is present in about 9% of SQSTM1 mutation carriers by the fifth decade."
Bone-scan screening of carriers in the ZiPP cohort dates the onset of bone disease.
PMID:39142003 SUPPORT Human Clinical
"These twenty-four patients (75% males) had late-onset (52,6 ± 10,1 years), mainly asymmetric, distal ankle and hand finger extension weakness (75%), mild CK elevation (82.4%) and myopathic EMG."
Gives the late age of onset of the digenic myopathy.
Progressive neurodegeneration
The bone presentation is focal and treatable, whereas ALS, FTD and the myopathy progress. In one ALS cohort, SQSTM1 variant carriers progressed faster to death or tracheostomy than non-carriers.
Show evidence (1 reference)
PMID:25708934 SUPPORT Human Clinical
"Notably, the ΔFS analysis revealed that the risk of death or tracheostomy was significantly increased in SQSTM1 mutation carriers (p < 0.05)."
Faster progression of SQSTM1-related ALS.
🔬

Clinical Trials

1
ISRCTN11616770 NOT_APPLICABLE COMPLETED
ZiPP: genetic testing of relatives of people with Paget disease of bone, then a double-blind randomised comparison of a single zoledronic acid infusion with placebo in SQSTM1 variant carriers, to prevent the development and progression of pagetic lesions.
Target Phenotypes: Paget disease of bone HP:0034159 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Paget disease of bone (HP:0034159). HP:0034159 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ICTRP:ISRCTN11616770 SUPPORT Other
"Scientific title: Randomised trial of genetic testing and targeted zoledronic acid therapy to prevent SQSTM1-mediated Paget's disease"
WHO ICTRP registration record establishing the trial's identity and its SQSTM1 carrier population.
{ }

Source YAML

click to show 
name: SQSTM1-related Multisystem Proteinopathy
creation_date: "2026-10-12T14:48:06Z"
category: Mendelian
description: >-
  SQSTM1-related multisystem proteinopathy (MSP4) is an adult-onset, autosomal
  dominant disorder caused by heterozygous variants in SQSTM1, which encodes
  the ubiquitin-binding selective-autophagy receptor and signalling scaffold
  p62/sequestosome-1. The same gene, and in some families the same allele
  (most often p.Pro392Leu), produces three clinical presentations with strongly
  variable penetrance: Paget disease of bone (PDB3), frontotemporal dementia
  and/or amyotrophic lateral sclerosis (FTDALS3), and a late-onset distal
  myopathy with rimmed vacuoles (DMRV). They occur alone or together within a
  family or an individual. The brain, spinal cord and muscle presentations
  share a pathology of p62- and TDP-43-positive ubiquitinated inclusions,
  consistent with failed p62-mediated clearance of ubiquitinated cargo. The
  bone presentation is driven by osteoclast precursors that are hypersensitive
  to RANKL with enhanced NF-kB signalling, and the extent to which it shares
  the autophagy lesion of the neuromuscular presentations is not settled. The
  myopathy is frequently digenic, with the TIA1 p.Asn357Ser variant co-inherited
  alongside the SQSTM1 variant. This entry covers the dominant, heterozygous
  disease only. Biallelic loss-of-function SQSTM1 variants cause a different,
  recessive childhood-onset neurodegeneration with ataxia, dystonia and gaze
  palsy, curated separately as SQSTM1-Related_Childhood-Onset_Neurodegeneration.
notes: >-
  Lumped at the gene level with the three MONDO descendants of MONDO:0800464
  (PDB3, FTDALS3 and DMRV) as subtypes, because they are allelic presentations
  of one dominant disorder that co-occur in families and in individuals; the
  ClinGen ALS gene curation expert panel made the same lumping decision for
  SQSTM1, while splitting off the recessive childhood-onset disease. The PDB3
  subtype is also a subtype row of the Paget_Disease_of_Bone entry, which
  models the bone arm in more detail (osteoclast biology, focal lesion
  evolution, environmental triggers) and remains the place to curate PDB
  itself; the row here is kept as an ordinary subtype rather than a curated_in
  pointer, because a pointer would claim that PDB3 is curated in full as its
  own entry, and it is not. The GeneReviews chapter "Multisystem Proteinopathy"
  (PMID:20301649) lists SQSTM1 among its genes only from its September 2026
  revision; earlier versions cover VCP, HNRNPA1 and HNRNPA2B1. It is tagged as
  the GeneReviews baseline but not quoted.
disease_term:
  preferred_term: SQSTM1-related multisystem proteinopathy
  term:
    id: MONDO:0800464
    label: SQSTM1-related multisystem proteinopathy
synonyms:
- MSP4
- multisystem proteinopathy 4
- SQSTM1-related MSP
parents:
- Multisystem Proteinopathy
- Neuromuscular Disorder
- Neurodegenerative Disorders
has_subtypes:
- name: PDB3
  display_name: Paget disease of bone 3 (SQSTM1)
  description: >-
    Focal, often polyostotic Paget disease of bone caused by heterozygous
    SQSTM1 variants that cluster in and around the C-terminal ubiquitin-associated
    (UBA) domain, recurrently p.Pro392Leu. It is the commonest and best-penetrant
    presentation; carriers are diagnosed earlier and with more affected bones
    than patients without a variant. Also carried as a subtype row of the
    Paget_Disease_of_Bone entry.
  genes:
  - preferred_term: SQSTM1
    term:
      id: hgnc:11280
      label: SQSTM1
  subtype_term:
    preferred_term: Paget disease of bone 3
    term:
      id: MONDO:0008176
      label: Paget disease of bone 3
  evidence:
  - reference: PMID:12374763
    reference_title: "Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These studies confirm that mutations affecting the ubiquitin-binding
      domain of SQSTM1 are a common cause of familial and sporadic Paget's
      disease of bone.
    explanation: >-
      Mutation screening of familial and sporadic PDB establishes UBA-domain
      SQSTM1 variants as the cause of this subtype.
  - reference: PMID:11992264
    reference_title: "Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data demonstrate that two independent mutational events at the same
      position in SQSTM1/p62 caused PDB in a high proportion of French Canadian
      patients.
    explanation: >-
      The original identification of the recurrent P392L allele in PDB families
      mapped to the PDB3 locus.
- name: FTDALS3
  display_name: Frontotemporal dementia and/or amyotrophic lateral sclerosis 3
  description: >-
    Behavioural-variant frontotemporal dementia, amyotrophic lateral sclerosis,
    or both, in carriers of heterozygous SQSTM1 variants. ALS/FTD-associated
    variants are spread across the whole protein, not only the UBA domain, and
    some (p.Pro392Leu, p.Pro387Leu, p.Ala381Val) are shared with PDB. Many
    patients are sporadic, which is attributed to reduced penetrance.
  genes:
  - preferred_term: SQSTM1
    term:
      id: hgnc:11280
      label: SQSTM1
  subtype_term:
    preferred_term: frontotemporal dementia and/or amyotrophic lateral sclerosis 3
    term:
      id: MONDO:0014640
      label: frontotemporal dementia and/or amyotrophic lateral sclerosis 3
  evidence:
  - reference: PMID:22084127
    reference_title: "SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 10 novel SQSTM1 mutations (9 heterozygous missense and 1
      deletion) in 15 patients (6 with familial ALS and 9 with sporadic ALS).
    explanation: >-
      First case-control screen linking heterozygous SQSTM1 variants to
      familial and sporadic ALS.
  - reference: PMID:24042580
    reference_title: "SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To our knowledge, this is the first study that clearly demonstrates a
      segregation of a SQSTM1 mutation with dementia in 2 families, F297 and
      FR1324.
    explanation: >-
      Family segregation of SQSTM1 variants with frontotemporal dementia.
  - reference: PMID:22972638
    reference_title: "SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 6 missense mutations in the coding region of SQSTM1 in
      patients with either FTLD or ALS, none of which were found in healthy
      controls or patients with PDB.
    explanation: >-
      Independent cohort showing SQSTM1 missense variants in FTLD and ALS.
- name: DMRV
  display_name: Distal myopathy with rimmed vacuoles (SQSTM1)
  description: >-
    Late-onset, often asymmetric distal myopathy with ankle dorsiflexion and
    finger extensor weakness, mildly raised creatine kinase and rimmed vacuoles
    containing p62 and TDP-43. First described with the SQSTM1 c.1165+1G>A
    splice variant, which can cause myopathy without bone or brain involvement.
    Most subsequently reported patients also carry TIA1 p.Asn357Ser, and the
    myopathy is then considered digenic. A frameshift variant has also been
    reported with a proximal, limb-girdle myopathy with rimmed vacuoles.
  genes:
  - preferred_term: SQSTM1
    term:
      id: hgnc:11280
      label: SQSTM1
  - preferred_term: TIA1
    description: >-
      The p.Asn357Ser variant is co-inherited with the SQSTM1 variant in most
      reported patients with the myopathy.
    term:
      id: hgnc:11802
      label: TIA1
  subtype_term:
    preferred_term: myopathy, distal, with rimmed vacuoles
    term:
      id: MONDO:0014945
      label: myopathy, distal, with rimmed vacuoles
  inheritance:
  - name: Digenic inheritance
    inheritance_term:
      preferred_term: Digenic inheritance
      term:
        id: HP:0010984
        label: Digenic inheritance
    description: >-
      Most patients with SQSTM1-related distal myopathy carry a heterozygous
      UBA-domain SQSTM1 variant (most often p.Pro392Leu) together with the TIA1
      p.Asn357Ser variant; the TIA1 variant is proposed to determine the
      myodegenerative presentation of the SQSTM1 variant.
    evidence:
    - reference: PMID:39142003
      reference_title: "Defining the landscape of TIA1 and SQSTM1 digenic myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The TIA1 p.Asn357Ser variant was present in all patients and the SQSTM1
        p.Pro392Leu was the most frequent (71%) of the four reported SQSTM1
        variants.
      explanation: >-
        A 24-patient series and literature review finds both variants in every
        patient with the digenic myopathy.
    - reference: PMID:38016875
      reference_title: "Distal myopathy due to digenic inheritance of TIA1 and SQSTM1 variants in two unrelated Spanish patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Digenic inheritance is supported by evidence from unrelated pedigrees
        and a plausible biological interaction between both proteins in protein
        quality control processes.
      explanation: >-
        States the basis for treating the myopathy as digenic.
  evidence:
  - reference: PMID:26208961
    reference_title: "SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected patients had late-onset distal lower extremity weakness,
      myopathic features on EMG, and muscle pathology demonstrating rimmed
      vacuoles with both TAR DNA-binding protein 43 and SQSTM1 inclusions.
    explanation: >-
      The founding description of SQSTM1 distal myopathy with rimmed vacuoles.
  - reference: PMID:26208961
    reference_title: "SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, the patients described in this study did not have evidence of
      PDB, ALS, or FTD, suggesting that myopathy can occur in isolation with
      c.1165+1 G>A SQSTM1 variant.
    explanation: >-
      Shows the myopathy can be the sole manifestation.
  - reference: PMID:36998782
    reference_title: "Frameshift mutation in SQSTM1 causes proximal myopathy with rimmed vacuoles: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Herein, we report a new phenotype of SQSTM1-associated proteinopathy, a
      novel frameshift mutation in SQSTM1 causing proximal MRV.
    explanation: >-
      Extends the muscle presentation to proximal weakness.
  - reference: PMID:29457785
    reference_title: "TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we provide evidence that a TIA1 (p.N357S) variant dictates a
      myodegenerative phenotype when inherited, along with a pathogenic SQSTM1
      mutation.
    explanation: >-
      Genetic evidence that co-inheritance of TIA1 p.N357S with an SQSTM1
      variant determines the myopathic presentation.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  description: >-
    Heterozygous SQSTM1 variants segregate dominantly with disease, but
    penetrance of each presentation is incomplete and age-dependent, so many
    carriers present as sporadic cases and relatives with the same variant may
    show different presentations.
  evidence:
  - reference: PMID:26208961
    reference_title: "SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Similar to mutations in VCP, dominantly inherited mutations in SQSTM1 are
      now associated with rimmed vacuolar myopathy, Paget disease of bone,
      amyotrophic lateral sclerosis, and frontotemporal dementia.
    explanation: >-
      States dominant inheritance across all four presentations.
  - reference: PMID:26208961
    reference_title: "SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The identification of SQSTM1 mutations in sporadic disease is likely due
      to its reduced penetrance.
    explanation: >-
      Supports incomplete penetrance.
  - reference: PMID:17229007
    reference_title: "Sequestosome 1: mutation frequencies, haplotypes, and phenotypes in familial Paget's disease of bone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Finally, the P392L mutation is transmitted as an autosomal dominant trait
      in the Quebecois families, with a high but incomplete penetrance peaking
      after age 60.
    explanation: >-
      Age-dependent, incomplete penetrance of P392L for PDB.
  - reference: PMID:24042580
    reference_title: "SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 4 heterozygous missense mutations in 4 unrelated families
      with FTD; only 1 family had clinical symptoms of Paget disease of bone,
      and only 1 family had clinical symptoms of FTD-ALS, possibly owing to the
      low penetrance of some of the clinical manifestations.
    explanation: >-
      Heterozygous variants in FTD families with variable, low-penetrance
      expression of the other presentations.
progression:
- phase: Adult-onset presentation
  notes: >-
    All three presentations begin in adulthood. In SQSTM1 carriers screened
    from PDB families, asymptomatic pagetic lesions are already present in
    about 9% by the fifth decade; dementia and myopathy typically begin in the
    sixth decade or later.
  evidence:
  - reference: PMID:32176830
    reference_title: "Characteristics of Early Paget's Disease in SQSTM1 Mutation Carriers: Baseline Analysis of the ZiPP Study Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Asymptomatic PDB is present in about 9% of SQSTM1 mutation carriers by
      the fifth decade.
    explanation: >-
      Bone-scan screening of carriers in the ZiPP cohort dates the onset of
      bone disease.
  - reference: PMID:39142003
    reference_title: "Defining the landscape of TIA1 and SQSTM1 digenic myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These twenty-four patients (75% males) had late-onset (52,6 ± 10,1 years),
      mainly asymmetric, distal ankle and hand finger extension weakness (75%),
      mild CK elevation (82.4%) and myopathic EMG.
    explanation: >-
      Gives the late age of onset of the digenic myopathy.
- phase: Progressive neurodegeneration
  notes: >-
    The bone presentation is focal and treatable, whereas ALS, FTD and the
    myopathy progress. In one ALS cohort, SQSTM1 variant carriers progressed
    faster to death or tracheostomy than non-carriers.
  evidence:
  - reference: PMID:25708934
    reference_title: "Six SQSTM1 mutations in a Chinese amyotrophic lateral sclerosis cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, the ΔFS analysis revealed that the risk of death or tracheostomy
      was significantly increased in SQSTM1 mutation carriers (p < 0.05).
    explanation: >-
      Faster progression of SQSTM1-related ALS.
pathophysiology:
- name: Heterozygous SQSTM1 Variant Alters p62 Domains
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    p62 is a multidomain scaffold: an N-terminal PB1 oligomerisation domain, a
    TRAF6-binding region, an LC3-interacting region (LIR) that docks it to the
    forming autophagosome, a KEAP1-interacting region (KIR), and a C-terminal
    UBA domain that binds ubiquitinated cargo. PDB-associated variants cluster
    in and around the UBA domain, whereas ALS/FTD-associated variants are
    distributed across the protein, including the LIR and KIR. Several
    alleles, p.Pro392Leu above all, occur in both groups. Which presentation an
    allele produces is therefore only partly predicted by where it lies.
  genes:
  - preferred_term: SQSTM1
    term:
      id: hgnc:11280
      label: SQSTM1
  genetic_context:
    gene:
      preferred_term: SQSTM1
      term:
        id: hgnc:11280
        label: SQSTM1
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
  evidence:
  - reference: PMID:27554286
    reference_title: "ALS-FTLD associated mutations of SQSTM1 impact on Keap1-Nrf2 signalling."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SQSTM1 encodes the SQSTM1/p62 protein and the overwhelming majority of
      mutations associated with PDB cluster within and around the C-terminal
      ubiquitin-associated (UBA) domain, whereas mutations associated with
      ALS-FTLD occur more widely throughout the protein sequence
    explanation: >-
      Introduction of a functional study summarising the domain distribution of
      bone-associated and neurodegeneration-associated variants.
  - reference: PMID:17229007
    reference_title: "Sequestosome 1: mutation frequencies, haplotypes, and phenotypes in familial Paget's disease of bone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 14 mutations reported in SQSTM1/p62 all affect the
      ubiquitin-associated domain of the protein.
    explanation: >-
      The PDB-associated alleles known at the time all lie in the UBA domain.
  - reference: PMID:24486447
    reference_title: "SQSTM1 mutations--bridging Paget disease of bone and ALS/FTLD."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Although several SQSTM1 mutations are common to both ALS/FTLD and PDB,
      many are ALS/FTLD-specific.
    explanation: >-
      Review stating that some alleles are shared between the bone and
      neurodegenerative presentations and others are not.
  - reference: PMID:23942205
    reference_title: "Sequestosome-1 (SQSTM1) sequence variants in ALS cases in the UK: prevalence and coexistence of SQSTM1 mutations in ALS kindred with PDB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In one p.(Pro392Leu) kindred, the carrier developed both ALS and Paget's
      disease of bone (PDB)
    explanation: >-
      The same allele can produce both the bone and the motor neuron
      presentation in one person.
  downstream:
  - target: Impaired p62-Mediated Selective Autophagy
    causal_link_type: DIRECT
    description: >-
      Variants in the UBA domain and LIR reduce binding of ubiquitinated cargo
      or of LC3, weakening p62's cargo-receptor function.
  - target: Impaired KEAP1-NRF2 Antioxidant Response
    causal_link_type: DIRECT
    description: >-
      Variants in or near the KIR reduce KEAP1 binding and NRF2 activation.
  - target: Enhanced RANKL-NF-kB Signalling in Osteoclast Precursors
    causal_link_type: DIRECT
    description: >-
      UBA-domain variants lose ubiquitin binding and increase NF-kB activation
      downstream of RANK in osteoclast precursors.
- name: Impaired p62-Mediated Selective Autophagy
  conforms_to: "disabled_macroautophagy#Failure of Cytoplasmic Quality Control"
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    p62 links ubiquitinated proteins to LC3 on the forming autophagosome so
    they can be degraded. Disease variants reduce LC3B recognition (LIR
    variants such as p.Leu341Val), reduce TBK1/ULK1-dependent phosphorylation
    of the UBA domain that activates cargo binding, or remove the UBA domain
    (the c.1165+1G>A splice product). The shared result is slower autophagic
    clearance of ubiquitinated proteins, the lesion the neurodegenerative and
    myopathic presentations are thought to share with VCP-, OPTN- and
    TBK1-related disease.
  genes:
  - preferred_term: SQSTM1
    term:
      id: hgnc:11280
      label: SQSTM1
  molecular_functions:
  - preferred_term: autophagy cargo adaptor activity
    modifier: DECREASED
    term:
      id: GO:0160247
      label: autophagy cargo adaptor activity
  - preferred_term: ubiquitin binding
    modifier: DECREASED
    term:
      id: GO:0043130
      label: ubiquitin binding
  biological_processes:
  - preferred_term: aggrephagy
    modifier: DECREASED
    term:
      id: GO:0035973
      label: aggrephagy
  - preferred_term: autophagy
    modifier: DECREASED
    term:
      id: GO:0006914
      label: autophagy
  evidence:
  - reference: PMID:26208961
    reference_title: "SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: >-
      SQSTM1 is an autophagic adaptor that shuttles aggregated and ubiquitinated
      proteins to the autophagosome for degradation via its C-terminal UBA
      domain.
    explanation: >-
      States the normal cargo-receptor function that disease variants impair.
  - reference: PMID:27158844
    reference_title: "Defective recognition of LC3B by mutant SQSTM1/p62 implicates impairment of autophagy as a pathogenic mechanism in ALS-FTLD."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here we show that although representing a conservative substitution and
      predicted to be benign, the ALS-associated L341V mutation of SQSTM1 is
      defective in recognition of LC3B.
    explanation: >-
      An ALS-associated LIR variant directly impairs docking of p62 to LC3B.
  - reference: PMID:27158844
    reference_title: "Defective recognition of LC3B by mutant SQSTM1/p62 implicates impairment of autophagy as a pathogenic mechanism in ALS-FTLD."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our data supports a model in which the L341V mutation limits the critical
      step of SQSTM1 recruitment to the phagophore.
    explanation: >-
      Functional consequence of the LIR variant in motor neuron-like cells.
  - reference: PMID:31362587
    reference_title: "ALS-FTLD-linked mutations of SQSTM1/p62 disrupt selective autophagy and NFE2L2/NRF2 anti-oxidative stress pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In contrast, ALS-FTLD-linked mutations of TBK1 or SQSTM1 reduce SQSTM1
      phosphorylation and compromise ubiquitinated cargo binding and clearance.
    explanation: >-
      ALS/FTD-linked SQSTM1 variants impair ubiquitinated cargo clearance in
      cells.
  downstream:
  - target: p62- and TDP-43-Positive Ubiquitinated Inclusions
    causal_link_type: DIRECT
    description: >-
      Uncleared ubiquitinated proteins accumulate with p62 and TDP-43 in
      neurons and myofibres.
  - target: Persistent Stress Granules
    causal_link_type: DIRECT
    description: >-
      p62 participates in stress granule clearance; mutant or depleted p62
      slows it.
- name: Impaired KEAP1-NRF2 Antioxidant Response
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  subtypes:
  - FTDALS3
  description: >-
    p62 binds KEAP1 through its KIR and so releases NRF2 to activate
    antioxidant genes. ALS/FTD variants in or next to the KIR (p.Pro348Leu,
    p.Gly351Ala, p.Gly427Arg through loss of Ser351 phosphorylation) reduce
    KEAP1 binding and NRF2 target-gene expression, and p.Gly427Arg increases
    TDP-43-associated stress granule formation under oxidative stress. Shown in
    cell models for a subset of neurodegeneration-associated alleles only.
  genes:
  - preferred_term: SQSTM1
    term:
      id: hgnc:11280
      label: SQSTM1
  biological_processes:
  - preferred_term: cellular response to oxidative stress
    modifier: DECREASED
    term:
      id: GO:0034599
      label: cellular response to oxidative stress
  evidence:
  - reference: PMID:27554286
    reference_title: "ALS-FTLD associated mutations of SQSTM1 impact on Keap1-Nrf2 signalling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Consistent with impaired Keap1 binding, the P348L and G351A KIR mutants
      showed reduced ability to activate Nrf2 signalling compared to wild-type
      SQSTM1/p62 in antioxidant response element (ARE)-luciferase reporter
      assays.
    explanation: >-
      KIR variants found in ALS/FTD reduce NRF2 activation in reporter assays.
  - reference: PMID:31362587
    reference_title: "ALS-FTLD-linked mutations of SQSTM1/p62 disrupt selective autophagy and NFE2L2/NRF2 anti-oxidative stress pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Moreover, disease mutation SQSTM1G427R abolishes phosphorylation of
      Ser351 and impairs KEAP1-SQSTM1 interaction, thus diminishing
      NFE2L2/Nrf2-targeted gene expression and increasing TARDBP/TDP-43
      associated stress granule formation under oxidative stress.
    explanation: >-
      A UBA-domain ALS/FTD variant disrupts KEAP1 binding and NRF2 signalling.
  downstream:
  - target: Persistent Stress Granules
    causal_link_type: DIRECT
    description: >-
      Under oxidative stress the G427R variant increases TDP-43-associated
      stress granule formation.
- name: Persistent Stress Granules
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Stress granules are transient ribonucleoprotein condensates that must be
    disassembled, partly by autophagy, once stress resolves. Mutant or depleted
    p62 slows their clearance. The TIA1 p.Asn357Ser variant enhances TIA1 phase
    separation, and granules made with it persist, bind more p62 and accumulate
    ubiquitinated and aggregated proteins. Co-expression of mutant TIA1 and
    mutant SQSTM1 in myoblasts is synergistically toxic, which is the proposed
    basis of the digenic myopathy.
  genes:
  - preferred_term: SQSTM1
    term:
      id: hgnc:11280
      label: SQSTM1
  - preferred_term: TIA1
    term:
      id: hgnc:11802
      label: TIA1
  biological_processes:
  - preferred_term: cytoplasmic stress granule disassembly
    modifier: DECREASED
    term:
      id: GO:0035617
      label: cytoplasmic stress granule disassembly
  evidence:
  - reference: PMID:29457785
    reference_title: "TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Depletion of SQSTM1 or the introduction of a mutant version of SQSTM1
      similarly impairs SG dynamics.
    explanation: >-
      Mutant SQSTM1 impairs stress granule dynamics in cells.
  - reference: PMID:29457785
    reference_title: "TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Synergistic expression of the TIA1-N357S variant and a SQSTM1-A390X
      mutation in myoblasts leads to impaired SG clearance and myotoxicity
      relative to control myoblasts.
    explanation: >-
      Combined TIA1 and SQSTM1 variants impair stress granule clearance and are
      toxic to muscle cells.
  - reference: PMID:33145792
    reference_title: "Multisystem proteinopathy: Where myopathy and motor neuron disease converge."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      all of which share disruption of RNA stress granule function and
      autophagic degradation.
    explanation: >-
      Review placing stress granule and autophagy defects at the centre of the
      multisystem proteinopathies including SQSTM1.
  downstream:
  - target: p62- and TDP-43-Positive Ubiquitinated Inclusions
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Persistent granules accumulate ubiquitin conjugates and aggregated
      proteins.
  - target: Rimmed Vacuolar Myofibre Degeneration
    causal_link_type: DIRECT
    description: >-
      Impaired stress granule clearance with mutant TIA1 and SQSTM1 is toxic
      to myoblasts.
- name: p62- and TDP-43-Positive Ubiquitinated Inclusions
  conforms_to: "loss_of_proteostasis#Misfolded-Protein Aggregation"
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The unifying pathology of the neurological and muscle presentations:
    ubiquitinated inclusions containing p62 and TDP-43 in motor neurons, in
    frontal cortex neurons and glia (FTLD-TDP), and in vacuolated myofibres.
    The aggregate species substituted here for the module's generic misfolded
    protein are p62 itself and TDP-43.
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  - preferred_term: cerebral cortex neuron
    term:
      id: CL:0010012
      label: cerebral cortex neuron
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  cellular_components:
  - preferred_term: p62 and TDP-43 inclusion
    term:
      id: GO:0016234
      label: inclusion body
  evidence:
  - reference: PMID:23417734
    reference_title: "Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neuropathology analysis of three patients carrying SQSTM1 variants
      revealed the presence of large round p62 inclusions in motor neurons, and
      immunoblot analysis showed an increased p62 and TDP-43 protein levels in
      the spinal cord.
    explanation: >-
      Autopsy evidence of p62 inclusions and TDP-43 accumulation in SQSTM1 ALS.
  - reference: PMID:26234378
    reference_title: "Clinicopathological description of two cases with SQSTM1 gene mutation associated with frontotemporal dementia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present study supports previous observations on amyotrophic lateral
      sclerosis (ALS) that SQSTM1 mutations consistently associate with TDP-43
      pathology.
    explanation: >-
      Clinicopathological FTD cases with SQSTM1 variants show TDP-43 pathology.
  - reference: PMID:26208961
    reference_title: "SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disparate phenotypes in muscle, brain, spinal cord, and bone are
      unified by the pathologic accumulation of ubiquitin and TDP-43.
    explanation: >-
      Places the shared ubiquitin and TDP-43 pathology across tissues.
  - reference: PMID:39142003
    reference_title: "Defining the landscape of TIA1 and SQSTM1 digenic myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle biopsy showed rimmed vacuoles (44.4%), myofibrillar
      disorganization (16.7%) or both (38.9%), with P62/TDP43 aggregates.
    explanation: >-
      p62 and TDP-43 aggregates in muscle of the digenic myopathy.
  downstream:
  - target: Upper and Lower Motor Neuron Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Frontotemporal Cortical Neurodegeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Rimmed Vacuolar Myofibre Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Upper and Lower Motor Neuron Degeneration
  conforms_to: "tdp43_proteinopathy#Selective Neuronal Dysfunction and Loss"
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  subtypes:
  - FTDALS3
  description: >-
    Degeneration of upper and lower motor neurons with p62 and TDP-43
    inclusions in spinal motor neurons, producing ALS alone or combined with
    frontotemporal dementia.
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  evidence:
  - reference: PMID:22084127
    reference_title: "SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings provide evidence of a direct genetic role for p62 in ALS
      pathogenesis
    explanation: >-
      Links SQSTM1 variants to motor neuron disease.
  - reference: PMID:23417734
    reference_title: "Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neuropathology analysis of three patients carrying SQSTM1 variants
      revealed the presence of large round p62 inclusions in motor neurons, and
      immunoblot analysis showed an increased p62 and TDP-43 protein levels in
      the spinal cord.
    explanation: >-
      Motor neurons are the site of p62 inclusion pathology in SQSTM1 ALS.
  downstream:
  - target: Amyotrophic lateral sclerosis
    causal_link_type: DIRECT
  - target: Fasciculations
    causal_link_type: DIRECT
  - target: Dysarthria
    causal_link_type: DIRECT
- name: Frontotemporal Cortical Neurodegeneration
  conforms_to: "tdp43_proteinopathy#Selective Neuronal Dysfunction and Loss"
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  subtypes:
  - FTDALS3
  description: >-
    Frontal and temporal lobar degeneration with TDP-43 pathology (type B in
    the best-characterised case, with oligodendroglial inclusions), seen on
    imaging as bilateral frontal or perisylvian atrophy with frontotemporal
    hypoperfusion.
  cell_types:
  - preferred_term: cerebral cortex neuron
    term:
      id: CL:0010012
      label: cerebral cortex neuron
  evidence:
  - reference: PMID:26234378
    reference_title: "Clinicopathological description of two cases with SQSTM1 gene mutation associated with frontotemporal dementia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TDP-43 pathology was consistent with the features of type B of FTLD-TDP
      pathology.
    explanation: >-
      Neuropathology of an SQSTM1 p.Glu396* carrier with behavioural FTD.
  - reference: PMID:24042580
    reference_title: "SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, brain imaging revealed bilateral frontal or predominantly
      perisylvian atrophy, which was associated with callosal and
      periventricular T2-weighted white matter hypersignals that were moderate
      but present in all the cases.
    explanation: >-
      Imaging shows frontotemporal atrophy in SQSTM1 FTD families.
  downstream:
  - target: Frontotemporal dementia
    causal_link_type: DIRECT
  - target: Disinhibition
    causal_link_type: DIRECT
  - target: Apathy
    causal_link_type: DIRECT
  - target: Impaired executive functioning
    causal_link_type: DIRECT
  - target: Polyphagia
    causal_link_type: DIRECT
  - target: Parkinsonism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cognitive impairment
    causal_link_type: DIRECT
- name: Rimmed Vacuolar Myofibre Degeneration
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  subtypes:
  - DMRV
  description: >-
    Myopathic degeneration of distal limb muscles with rimmed vacuoles,
    myofibrillar disorganisation, Z-band streaming and fibres containing p62,
    TDP-43 and LC3. With the c.1165+1G>A splice variant, a UBA-truncated and a
    PEST2-deleted p62 are made; the PEST2-deleted form builds large
    sarcoplasmic inclusions in muscle.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  evidence:
  - reference: PMID:26208961
    reference_title: "SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected patients had late-onset distal lower extremity weakness,
      myopathic features on EMG, and muscle pathology demonstrating rimmed
      vacuoles with both TAR DNA-binding protein 43 and SQSTM1 inclusions.
    explanation: >-
      Muscle pathology of the SQSTM1 myopathy.
  - reference: PMID:26208961
    reference_title: "SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electron microscopy (EM) demonstrated large foci of myofibrillar
      disorganization and Z-band streaming (figure 2, G and H).
    explanation: >-
      Ultrastructural myofibrillar damage in a patient biopsy.
  downstream:
  - target: Distal muscle weakness
    causal_link_type: DIRECT
  - target: Foot dorsiflexor weakness
    causal_link_type: DIRECT
  - target: Weakness of long finger extensor muscles
    causal_link_type: DIRECT
  - target: Scapular winging
    causal_link_type: DIRECT
  - target: Rimmed vacuoles
    causal_link_type: DIRECT
  - target: Z-band streaming
    causal_link_type: DIRECT
  - target: Elevated circulating creatine kinase
    causal_link_type: DIRECT
  - target: Myopathic EMG
    causal_link_type: DIRECT
- name: Enhanced RANKL-NF-kB Signalling in Osteoclast Precursors
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  subtypes:
  - PDB3
  description: >-
    UBA-domain variants impair p62 ubiquitin binding and raise basal and
    RANKL-induced NF-kB activation in osteoclast precursors, which become
    hypersensitive to RANKL and form larger osteoclasts with more nuclei that
    resorb more bone. The degree of NF-kB activation by a given UBA variant
    tracks the number of affected bones in patients. Osteoclast precursors from
    knock-in mice also show markers of dysregulated autophagy, so this arm is
    not purely a signalling defect.
  genes:
  - preferred_term: SQSTM1
    term:
      id: hgnc:11280
      label: SQSTM1
  cell_types:
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  molecular_functions:
  - preferred_term: ubiquitin binding
    modifier: DECREASED
    term:
      id: GO:0043130
      label: ubiquitin binding
  biological_processes:
  - preferred_term: positive regulation of canonical NF-kappaB signal transduction
    modifier: INCREASED
    term:
      id: GO:0043123
      label: positive regulation of canonical NF-kappaB signal transduction
  - preferred_term: positive regulation of osteoclast differentiation
    modifier: INCREASED
    term:
      id: GO:0045672
      label: positive regulation of osteoclast differentiation
  evidence:
  - reference: PMID:24642144
    reference_title: "Paget disease of bone-associated UBA domain mutations of SQSTM1 exert distinct effects on protein structure and function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Both impaired SQSTM1's ubiquitin-binding function in pull-down assays and
      resulted in activation of basal NF-κB signalling, compared to wild-type,
      in reporter assays.
    explanation: >-
      Two PDB UBA-domain variants lose ubiquitin binding and activate NF-kB.
  - reference: PMID:24642144
    reference_title: "Paget disease of bone-associated UBA domain mutations of SQSTM1 exert distinct effects on protein structure and function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found evidence for a relationship between the ability of different UBA
      domain mutants to activate NF-κB signalling in vitro and number of
      affected sites in vivo in 1152 PDB patients from the UK and Italy
    explanation: >-
      NF-kB activation by an allele relates to disease extent in patients.
  - reference: PMID:16813535
    reference_title: "A novel mutation (K378X) in the sequestosome 1 gene associated with increased NF-kappaB signaling and Paget's disease of bone with a severe phenotype."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      p62 mutants increased NF-kappaB activation and significantly potentiated
      osteoclast formation and bone resorption in human primary cell cultures.
    explanation: >-
      Mutant p62 enhances NF-kB activation and osteoclastogenesis in human
      cells.
  - reference: PMID:21515589
    reference_title: "A point mutation in the ubiquitin-associated domain of SQSMT1 is sufficient to cause a Paget's disease-like disorder in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Osteoclast precursors from P394L mutant mice had increased sensitivity to
      RANKL in vitro resulting in the generation of osteoclasts that were larger
      and more nucleated than those generated from wild-type littermates.
    explanation: >-
      Knock-in of the murine P392L equivalent makes osteoclast precursors
      RANKL-hypersensitive.
  - reference: PMID:21515589
    reference_title: "A point mutation in the ubiquitin-associated domain of SQSMT1 is sufficient to cause a Paget's disease-like disorder in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      There was increased expression of sqstm1, autophagy-related gene 5 (atg5)
      and light chain 3 gene (lc3) in osteoclast precursors and increased LC3-II
      protein levels in Bafilomycin-treated osteoclasts from P394L mutant mice
      compared with wild-type suggesting dysregulation of autophagy and enhanced
      autophagosome formation.
    explanation: >-
      Autophagy markers are also altered in mutant osteoclast lineage cells.
  downstream:
  - target: Focal Accelerated Bone Turnover
    causal_link_type: DIRECT
- name: Focal Accelerated Bone Turnover
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  subtypes:
  - PDB3
  description: >-
    Focal lesions with increased resorption and disorganised formation of
    woven bone, the pagetic lesion. Whether the germline UBA variant is
    sufficient on its own is contested: one P394L knock-in mouse line developed
    focal pagetic lesions without any other trigger, while an independently
    made P394L knock-in line had more osteoclasts but no lesions unless measles
    virus nucleocapsid protein was also expressed in osteoclasts.
  cell_types:
  - preferred_term: multinuclear osteoclast
    term:
      id: CL:0000779
      label: multinuclear osteoclast
  evidence:
  - reference: PMID:21515589
    reference_title: "A point mutation in the ubiquitin-associated domain of SQSMT1 is sufficient to cause a Paget's disease-like disorder in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Lesions predominantly affected the lower limbs in an asymmetric manner and
      were characterized by focal increases in bone turnover, with increased
      bone resorption and formation, disruption of the normal bone architecture
      and accumulation of woven bone.
    explanation: >-
      The pagetic lesion reproduced in knock-in mice.
  - reference: PMID:21515589
    reference_title: "A point mutation in the ubiquitin-associated domain of SQSMT1 is sufficient to cause a Paget's disease-like disorder in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These studies demonstrate that SQSTM1 mutations can cause a PDB-like
      skeletal disorder in the absence of an additional trigger
    explanation: >-
      The UBA variant is sufficient for the bone lesion in mice.
  - reference: PMID:16877352
    reference_title: "p62 ubiquitin binding-associated domain mediated the receptor activator of nuclear factor-kappaB ligand-induced osteoclast formation: a new insight into the pathogenesis of Paget's disease of bone."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Overexpression of p62DeltaUBA potentiated the formation of abnormally
      large multinucleated osteoclasts and resorption of bone, reminiscent of
      PDB.
    explanation: >-
      Loss of the UBA domain produces pagetic-like osteoclasts in culture.
  - reference: PMID:24339057
    reference_title: "Increased IL-6 expression in osteoclasts is necessary but not sufficient for the development of Paget's disease of bone."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We previously generated p62(P394L) knock-in mice (p62KI) and found that
      although OCL numbers were increased, the mice did not develop pagetic
      lesions.
    explanation: >-
      An independent knock-in line contradicts the claim that the UBA variant
      alone is sufficient for the focal lesion.
  - reference: PMID:24339057
    reference_title: "Increased IL-6 expression in osteoclasts is necessary but not sufficient for the development of Paget's disease of bone."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      However, mice expressing both MVNP and p62KI developed more exuberant
      pagetic lesions than mice expressing MVNP alone.
    explanation: >-
      In that line the variant amplifies lesions driven by a second factor.
  downstream:
  - target: Paget disease of bone
    causal_link_type: DIRECT
  - target: Elevated circulating alkaline phosphatase
    causal_link_type: DIRECT
  - target: Bone pain
    causal_link_type: DIRECT
  - target: Bone deformity
    causal_link_type: DIRECT
  - target: Hearing impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Pagetic involvement of the skull, including the temporal bone, is the
      usual route to hearing loss in Paget disease of bone.
  - target: Osteosarcoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Bone pain
  category: Skeletal
  subtype: PDB3
  description: >-
    Pain arising from pagetic bone, the commonest reason a lesion comes to clinical attention.
  phenotype_term:
    preferred_term: Bone pain
    term:
      id: HP:0002653
      label: Bone pain
  evidence:
  - reference: PMID:38123339
    reference_title: "Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      These abnormalities can cause various complications including bone pain,
      deformity, pathological fractures, nerve compression syndromes, deafness,
      secondary osteoarthritis and osteosarcoma
    explanation: >-
      The ZiPP report's introduction lists bone pain among the complications of Paget disease of bone.
- name: Bone deformity
  category: Skeletal
  subtype: PDB3
  description: >-
    Deformity of affected bones, such as bowing of long bones or skull enlargement.
  phenotype_term:
    preferred_term: Bone deformity
    term:
      id: HP:0011842
      label: Abnormal skeletal morphology
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:38123339
    reference_title: "Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      These abnormalities can cause various complications including bone pain,
      deformity, pathological fractures, nerve compression syndromes, deafness,
      secondary osteoarthritis and osteosarcoma
    explanation: >-
      The ZiPP report's introduction lists deformity among the complications of Paget disease of bone.
- name: Hearing impairment
  category: Skeletal
  subtype: PDB3
  description: >-
    Hearing loss, mainly from pagetic involvement of the skull.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:38123339
    reference_title: "Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      These abnormalities can cause various complications including bone pain,
      deformity, pathological fractures, nerve compression syndromes, deafness,
      secondary osteoarthritis and osteosarcoma
    explanation: >-
      The ZiPP report's introduction lists deafness among the complications of Paget disease of bone.
- name: Osteosarcoma
  category: Skeletal
  subtype: PDB3
  description: >-
    A rare malignant complication arising in pagetic bone.
  phenotype_term:
    preferred_term: Osteosarcoma
    term:
      id: HP:0002669
      label: Osteosarcoma
  evidence:
  - reference: PMID:38123339
    reference_title: "Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      These abnormalities can cause various complications including bone pain,
      deformity, pathological fractures, nerve compression syndromes, deafness,
      secondary osteoarthritis and osteosarcoma
    explanation: >-
      The ZiPP report's introduction lists osteosarcoma among the complications of Paget disease of bone.
- name: Paget disease of bone
  category: Skeletal
  subtype: PDB3
  description: >-
    Focal, frequently polyostotic Paget disease of bone. SQSTM1 carriers are
    diagnosed earlier and have more affected bones than patients without a
    variant. Early lesions found by screening are asymptomatic.
  phenotype_term:
    preferred_term: Paget disease of bone
    term:
      id: HP:0034159
      label: Paget disease of bone
  evidence:
  - reference: PMID:12374763
    reference_title: "Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common mutation was the P392L change in exon 8, which was found
      in 13 of 68 families (19.1%).
    explanation: >-
      PDB families carrying the recurrent SQSTM1 variant.
  - reference: PMID:20499339
    reference_title: "Mutations of SQSTM1 are associated with severity and clinical outcome in paget disease of bone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutation carriers had an earlier age at diagnosis (59.4 ± 11.5 versus
      65.0 ± 10.4 years, p < .0001) and a greater number of affected bones (3.2
      ± 1.2 versus 2.1 ± 1.2, p < .001)
    explanation: >-
      SQSTM1-related PDB is earlier and more extensive.
- name: Increased susceptibility to fractures
  category: Skeletal
  subtype: PDB3
  description: >-
    Fractures were more frequent in SQSTM1 carriers with PDB over follow-up,
    though most occurred in bone not affected by Paget disease, so no causal
    edge from the pagetic lesion is drawn.
  phenotype_term:
    preferred_term: Increased susceptibility to fractures
    term:
      id: HP:0002659
      label: Increased susceptibility to fractures
  evidence:
  - reference: PMID:20499339
    reference_title: "Mutations of SQSTM1 are associated with severity and clinical outcome in paget disease of bone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During the study, fractures were more common in carriers (12.5% versus
      5.3%, p = .011), although most of these occurred in unaffected bone.
    explanation: >-
      Higher fracture rate in SQSTM1 carriers with PDB.
- name: Elevated circulating alkaline phosphatase
  category: Laboratory
  subtype: PDB3
  description: >-
    Serum alkaline phosphatase is higher in carriers with pagetic lesions, but
    it is an insensitive marker of early disease.
  phenotype_term:
    preferred_term: Elevated serum alkaline phosphatase
    term:
      id: HP:0003155
      label: Elevated circulating alkaline phosphatase concentration
  evidence:
  - reference: PMID:32176830
    reference_title: "Characteristics of Early Paget's Disease in SQSTM1 Mutation Carriers: Baseline Analysis of the ZiPP Study Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Serum concentrations of total alkaline phosphatase (ALP) normalized to the
      upper limit of normal in each center were higher in those with lesions
    explanation: >-
      ALP is raised in SQSTM1 carriers with PDB lesions.
- name: Frontotemporal dementia
  category: Neurological
  subtype: FTDALS3
  description: >-
    Behavioural-variant frontotemporal dementia, alone or with ALS or PDB in
    the same family; onset is often late.
  phenotype_term:
    preferred_term: Frontotemporal dementia
    term:
      id: HP:0002145
      label: Frontotemporal dementia
  evidence:
  - reference: PMID:24042580
    reference_title: "SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinically, all the families were affected by bvFTD,19 which was
      associated with ALS in family F480 (8% of the patients) and with PDB in
      family FR1324 (30% of the patients).
    explanation: >-
      Behavioural FTD in all four SQSTM1 families, variably with ALS or PDB.
- name: Disinhibition
  category: Behavioral
  subtype: FTDALS3
  phenotype_term:
    preferred_term: Disinhibition
    term:
      id: HP:0000734
      label: Disinhibition
  evidence:
  - reference: PMID:24042580
    reference_title: "SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He developed disinhibition, rituals, verbal stereotypies, indifference,
      social avoidance, apathy, and reduced verbal fluency but no ALS symptoms.
    explanation: >-
      Disinhibition in an SQSTM1 p.Ala381Val carrier with behavioural FTD.
- name: Apathy
  category: Behavioral
  subtype: FTDALS3
  phenotype_term:
    preferred_term: Apathy
    term:
      id: HP:0000741
      label: Apathy
  evidence:
  - reference: PMID:24042580
    reference_title: "SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He developed disinhibition, rituals, verbal stereotypies, indifference,
      social avoidance, apathy, and reduced verbal fluency but no ALS symptoms.
    explanation: >-
      Apathy in an SQSTM1 carrier with behavioural FTD.
- name: Polyphagia
  category: Behavioral
  subtype: FTDALS3
  description: Bulimia as an early behavioural sign of FTD.
  phenotype_term:
    preferred_term: Bulimia
    term:
      id: HP:0002591
      label: Polyphagia
  evidence:
  - reference: PMID:24042580
    reference_title: "SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      initially presented with indifference, disinhibited behavior, and
      bulimia
    explanation: >-
      Presenting behavioural features of the index patient of family F297.
- name: Impaired executive functioning
  category: Neurological
  subtype: FTDALS3
  phenotype_term:
    preferred_term: Executive dysfunction
    term:
      id: HP:0033051
      label: Impaired executive functioning
  evidence:
  - reference: PMID:24042580
    reference_title: "SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neuropsychological testing revealed executive dysfunction (Table 2).
    explanation: >-
      Executive dysfunction on testing in SQSTM1 FTD patients.
- name: Parkinsonism
  category: Neurological
  subtype: FTDALS3
  description: >-
    Extrapyramidal signs during the course of FTD in some carriers.
  phenotype_term:
    preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: PMID:24042580
    reference_title: "SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a limitation of voluntary downward gaze, and she developed extrapyramidal
      signs.
    explanation: >-
      Extrapyramidal signs in the F297 index patient.
- name: Cognitive impairment
  category: Neurological
  subtype: FTDALS3
  frequency: OCCASIONAL
  description: >-
    Among ALS patients carrying an SQSTM1 variant, about a quarter have
    comorbid cognitive impairment.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:39122262
    reference_title: "Genotype-phenotype correlation of SQSTM1 variants in patients with amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, 26% (5/19) of the patients with ALS with SQSTM1 variant in our
      cohort had comorbid cognitive impairment and 43% (3/7) of them had
      behavioural variant frontotemporal dementia (FTD).
    explanation: >-
      Frequency of cognitive impairment in SQSTM1-related ALS.
- name: Amyotrophic lateral sclerosis
  category: Neurological
  subtype: FTDALS3
  description: >-
    Familial or apparently sporadic ALS; SQSTM1 variants are found in about 2%
    of ALS patients across cohorts.
  phenotype_term:
    preferred_term: Amyotrophic lateral sclerosis
    term:
      id: HP:0007354
      label: Amyotrophic lateral sclerosis
  evidence:
  - reference: PMID:22084127
    reference_title: "SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 10 novel SQSTM1 mutations (9 heterozygous missense and 1
      deletion) in 15 patients (6 with familial ALS and 9 with sporadic ALS).
    explanation: >-
      ALS in SQSTM1 variant carriers.
  - reference: PMID:39122262
    reference_title: "Genotype-phenotype correlation of SQSTM1 variants in patients with amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our meta-analysis found a total frequency of SQSTM1 variants in 7183
      patients with ALS was 2.4%
    explanation: >-
      Frequency of SQSTM1 variants among ALS patients.
- name: Fasciculations
  category: Neurological
  subtype: FTDALS3
  phenotype_term:
    preferred_term: Fasciculations
    term:
      id: HP:0002380
      label: Fasciculations
  evidence:
  - reference: PMID:24042580
    reference_title: "SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He also had diffuse enhanced reflexes, a right-sided Babinski sign, a
      bilateral motor deficit, fasciculations, and amyotrophy predominantly
      affecting the upper limbs.
    explanation: >-
      Upper and lower motor neuron signs in the FTD-ALS proband of family F480.
- name: Dysarthria
  category: Neurological
  subtype: FTDALS3
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:24042580
    reference_title: "SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      he was examined and was revealed to have dysarthria and dysphonia with
      stuttering and buccofacial apraxia
    explanation: >-
      Bulbar involvement in the FTD-ALS proband.
- name: Distal muscle weakness
  category: Musculoskeletal
  subtype: DMRV
  description: >-
    Late-onset, mainly asymmetric distal weakness, often later involving the
    shoulder girdle.
  phenotype_term:
    preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
  evidence:
  - reference: PMID:26208961
    reference_title: "SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected patients had late-onset distal lower extremity weakness,
      myopathic features on EMG, and muscle pathology demonstrating rimmed
      vacuoles with both TAR DNA-binding protein 43 and SQSTM1 inclusions.
    explanation: >-
      Distal lower limb weakness in SQSTM1 myopathy.
- name: Foot dorsiflexor weakness
  category: Musculoskeletal
  subtype: DMRV
  phenotype_term:
    preferred_term: Ankle dorsiflexion weakness
    term:
      id: HP:0009027
      label: Foot dorsiflexor weakness
  evidence:
  - reference: PMID:26208961
    reference_title: "SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      developed right ankle dorsiflexion weakness at age 52
    explanation: >-
      Ankle dorsiflexion weakness as the presenting sign in the index family.
- name: Weakness of long finger extensor muscles
  category: Musculoskeletal
  subtype: DMRV
  frequency: FREQUENT
  description: >-
    Finger extension weakness; the frequency is from 24 patients with the
    digenic TIA1/SQSTM1 myopathy, counted together with ankle weakness.
  phenotype_term:
    preferred_term: Finger extensor weakness
    term:
      id: HP:0009077
      label: Weakness of long finger extensor muscles
  evidence:
  - reference: PMID:39142003
    reference_title: "Defining the landscape of TIA1 and SQSTM1 digenic myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mainly asymmetric, distal ankle and hand finger extension weakness (75%)
    explanation: >-
      Finger extension weakness in three quarters of digenic myopathy patients.
- name: Scapular winging
  category: Musculoskeletal
  subtype: DMRV
  phenotype_term:
    preferred_term: Scapular winging
    term:
      id: HP:0003691
      label: Scapular winging
  evidence:
  - reference: PMID:26208961
    reference_title: "SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild shoulder abduction weakness (left greater than right), bilateral
      scapular winging
    explanation: >-
      Scapular winging in the proband of the index family.
- name: Elevated circulating creatine kinase
  category: Laboratory
  subtype: DMRV
  frequency: VERY_FREQUENT
  description: Mild elevation of creatine kinase.
  phenotype_term:
    preferred_term: Mildly elevated creatine kinase
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:39142003
    reference_title: "Defining the landscape of TIA1 and SQSTM1 digenic myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild CK elevation (82.4%) and myopathic EMG
    explanation: >-
      Mild CK elevation in most digenic myopathy patients.
- name: Myopathic EMG
  category: Neurophysiological
  subtype: DMRV
  phenotype_term:
    preferred_term: Myopathic EMG
    term:
      id: HP:0003458
      label: 'EMG: myopathic abnormalities'
  evidence:
  - reference: PMID:39142003
    reference_title: "Defining the landscape of TIA1 and SQSTM1 digenic myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild CK elevation (82.4%) and myopathic EMG
    explanation: >-
      Myopathic EMG in the digenic myopathy series.
- name: Rimmed vacuoles
  category: Histopathology
  subtype: DMRV
  frequency: VERY_FREQUENT
  description: >-
    Rimmed vacuoles alone (44%) or with myofibrillar disorganisation (39%) in
    biopsies from the digenic myopathy series.
  phenotype_term:
    preferred_term: Rimmed vacuoles
    term:
      id: HP:0003805
      label: Rimmed vacuoles
  evidence:
  - reference: PMID:39142003
    reference_title: "Defining the landscape of TIA1 and SQSTM1 digenic myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle biopsy showed rimmed vacuoles (44.4%), myofibrillar
      disorganization (16.7%) or both (38.9%), with P62/TDP43 aggregates.
    explanation: >-
      Frequency of rimmed vacuoles on muscle biopsy.
- name: Z-band streaming
  category: Histopathology
  subtype: DMRV
  phenotype_term:
    preferred_term: Z-band streaming
    term:
      id: HP:0020203
      label: Z-band streaming
  evidence:
  - reference: PMID:26208961
    reference_title: "SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electron microscopy (EM) demonstrated large foci of myofibrillar
      disorganization and Z-band streaming (figure 2, G and H).
    explanation: >-
      Z-band streaming on electron microscopy of patient muscle.
genetic:
- name: SQSTM1
  gene_term:
    preferred_term: SQSTM1
    term:
      id: hgnc:11280
      label: SQSTM1
  variant_origin: GERMLINE
  features: >-
    Heterozygous missense, truncating and splice variants. PDB variants
    cluster in and around the UBA domain; ALS/FTD variants are spread across
    the protein. p.Pro392Leu is the commonest allele in PDB, recurs in ALS and
    FTD, and is the usual SQSTM1 allele in the digenic myopathy. The
    c.1165+1G>A splice variant has been reported in PDB, ALS with PDB, and
    isolated distal myopathy.
  examples:
  - p.Pro392Leu
  - c.1165+1G>A
  - p.Pro387Leu
  - p.Ala381Val
  - p.Leu341Val
  - p.Gly427Arg
  variants:
  - name: p.Pro392Leu
    description: >-
      Recurrent UBA-flanking missense variant; the most frequent SQSTM1 allele
      in PDB, also found in FTD, ALS and the digenic myopathy.
    evidence:
    - reference: PMID:11992264
      reference_title: "Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        led to the identification of a recurrent nonconservative change
        (P392L) flanking the ubiquitin-associated domain (UBA) (position
        394-440) of the protein that was not present in 291 control
        individuals.
      explanation: >-
        Identification of the recurrent PDB allele.
    - reference: PMID:23942205
      reference_title: "Sequestosome-1 (SQSTM1) sequence variants in ALS cases in the UK: prevalence and coexistence of SQSTM1 mutations in ALS kindred with PDB."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The occurrence of the same mutation in ALS and PDB is indicative of a
        common pathogenic pathway that converges on protein homeostasis.
      explanation: >-
        The same allele in ALS and PDB.
  - name: c.1165+1G>A
    description: >-
      Splice-donor variant in intron 7 producing UBA-truncated and
      PEST2-deleted p62; reported in PDB, ALS with PDB, and distal myopathy.
    evidence:
    - reference: PMID:26208961
      reference_title: "SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Sequencing identified a likely pathogenic c.1165+1 G>A splice donor
        variant in SQSTM1 in the affected members of 1 family and in an
        unrelated patient with sporadic distal myopathy.
      explanation: >-
        The splice variant in SQSTM1 distal myopathy.
  evidence:
  - reference: PMID:26208961
    reference_title: "SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have now demonstrated that SQSTM1 can cause a rimmed vacuolar myopathy
      in addition to ALS, FTD, and PDB and could thus be considered a
      multisystem proteinopathy or MSP4.
    explanation: >-
      Establishes SQSTM1 as a multisystem proteinopathy gene.
  - reference: PMID:29457785
    reference_title: "TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identical mutations in the autophagic adaptor SQSTM1 can cause varied
      penetrance of 4 distinct phenotypes
    explanation: >-
      The same SQSTM1 alleles underlie all four presentations.
  - reference: PMID:21515589
    reference_title: "A point mutation in the ubiquitin-associated domain of SQSMT1 is sufficient to cause a Paget's disease-like disorder in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These studies demonstrate that SQSTM1 mutations can cause a PDB-like
      skeletal disorder in the absence of an additional trigger
    explanation: >-
      In this knock-in line a single allele was sufficient for the bone
      presentation; an independent line was not (see Focal Accelerated Bone
      Turnover).
  - reference: CGGV:assertion_dae3327f-6381-44cc-8baa-8fa1fc0d31d5-2022-12-13T170000.000Z
    reference_title: "SQSTM1 / frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      we did not find a distinct difference between the molecular mechanism,
      phenotypic variability, or inheritance pattern of distal
      myopathy/myositis and FTD/ALS 3, nor a distinct difference between the
      molecular mechanism or inheritance pattern of Paget disease of bone 3
      and FTD/ALS 3; therefore, these diseases were lumped for the purposes
      of gene curation.
    explanation: >-
      ClinGen lumps the three dominant presentations into one gene curation,
      matching the lump made in this entry.
  gene_disease_validity:
  - validity_classification: MODERATE
    classified_by: CLINGEN
    subtype: FTDALS3
    external_id: CGGV:assertion_dae3327f-6381-44cc-8baa-8fa1fc0d31d5-2022-12-13T170000.000Z
    notes: >-
      ClinGen curated SQSTM1 for FTD/ALS 3 and lumped distal myopathy and PDB3
      into the same curation; the panel cites the lack of segregation data in
      ALS as what holds the classification at Moderate. Because this tier
      covers the lumped dominant disease and is below Strong, the record
      carries no CAUSATIVE relationship type, although segregation in PDB
      families is well documented.
    evidence:
    - reference: CGGV:assertion_dae3327f-6381-44cc-8baa-8fa1fc0d31d5-2022-12-13T170000.000Z
      reference_title: "SQSTM1 / frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (Moderate)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        SQSTM1 | HGNC:11280 | frontotemporal dementia and/or amyotrophic
        lateral sclerosis 3 | MONDO:0014640 | AD | Moderate
      explanation: >-
        ClinGen gene-disease validity row for SQSTM1 and FTD/ALS 3.
- name: TIA1
  gene_term:
    preferred_term: TIA1
    term:
      id: hgnc:11802
      label: TIA1
  relationship_type: MODIFIER
  subtype: DMRV
  features: >-
    The p.Asn357Ser variant, co-inherited with a pathogenic SQSTM1 variant,
    is proposed to determine the myopathic presentation. It is also enriched in
    distal myopathy patients without an SQSTM1 variant, consistent with a
    modifier.
  examples:
  - p.Asn357Ser
  evidence:
  - reference: PMID:29457785
    reference_title: "TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we provide evidence that a TIA1 (p.N357S) variant dictates a
      myodegenerative phenotype when inherited, along with a pathogenic SQSTM1
      mutation.
    explanation: >-
      TIA1 p.N357S as the determinant of the myopathic presentation.
  - reference: PMID:39142003
    reference_title: "Defining the landscape of TIA1 and SQSTM1 digenic myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We confirm an increased burden of the TIA1 p.Asn357Ser variant in distal
      myopathy patients which could act as a genetic modifier.
    explanation: >-
      Supports the modifier role.
diagnosis:
- name: SQSTM1 molecular genetic testing
  description: >-
    Sequencing of SQSTM1 confirms the diagnosis. In distal myopathy, TIA1
    should be tested together with SQSTM1, because most patients carry both
    variants.
  diagnosis_term:
    preferred_term: Genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:38016875
    reference_title: "Distal myopathy due to digenic inheritance of TIA1 and SQSTM1 variants in two unrelated Spanish patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical suspicion is necessary to seek both variants.
    explanation: >-
      Recommends testing for both the TIA1 and SQSTM1 variants.
- name: Radionuclide bone scan in carriers
  description: >-
    In SQSTM1 carriers, a radionuclide bone scan detects early, asymptomatic
    pagetic lesions; serum alkaline phosphatase is raised in those with lesions
    but misses many. Screening for PDB is recommended in SQSTM1 carriers with
    any presentation.
  diagnosis_term:
    preferred_term: Bone scan
    term:
      id: NCIT:C17646
      label: Bone Scan
  evidence:
  - reference: PMID:32176830
    reference_title: "Characteristics of Early Paget's Disease in SQSTM1 Mutation Carriers: Baseline Analysis of the ZiPP Study Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Asymptomatic PDB is present in about 9% of SQSTM1 mutation carriers by
      the fifth decade.
    explanation: >-
      Bone-scan screening of carriers detects asymptomatic lesions.
  - reference: PMID:32176830
    reference_title: "Characteristics of Early Paget's Disease in SQSTM1 Mutation Carriers: Baseline Analysis of the ZiPP Study Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the sensitivity of ALP and other markers in detecting lesions was poor
    explanation: >-
      Biochemical markers alone are insufficient for screening.
  - reference: PMID:36861178
    reference_title: "Multisystem proteinopathies (MSPs) and MSP-like disorders: Clinical-pathological-molecular spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Based on current literature, screening for PDB should be performed in
      patients with VCP, HNRNPA2B1, HNRNPA1, and SQSTM1 mutations
    explanation: >-
      Recommends PDB screening in SQSTM1 carriers.
- name: Muscle biopsy
  description: >-
    Shows a myopathy with rimmed vacuoles, myofibrillar disorganisation and
    p62/TDP-43 aggregates.
  diagnosis_term:
    preferred_term: Muscle biopsy
    term:
      id: NCIT:C51895
      label: Muscle Biopsy
  evidence:
  - reference: PMID:39142003
    reference_title: "Defining the landscape of TIA1 and SQSTM1 digenic myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle biopsy showed rimmed vacuoles (44.4%), myofibrillar
      disorganization (16.7%) or both (38.9%), with P62/TDP43 aggregates.
    explanation: >-
      Biopsy findings in the myopathy.
treatments:
- name: Zoledronic acid
  description: >-
    A single 5 mg infusion of zoledronic acid in SQSTM1 carriers identified by
    family screening was well tolerated, reduced bone turnover markers and
    prevented progression of early pagetic lesions in a randomised
    placebo-controlled trial (ZiPP); it was underpowered to show prevention of
    new lesions. No disease-modifying treatment exists for the neurological or
    muscle presentations.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: zoledronic acid
      term:
        id: CHEBI:46557
        label: zoledronic acid
  target_mechanisms:
  - target: Focal Accelerated Bone Turnover
    description: Bisphosphonate inhibition of osteoclastic bone resorption.
  evidence:
  - reference: PMID:38123339
    reference_title: "Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eight of the placebo group had a poor outcome (lesions which were new,
      unchanged or progressing) compared with none of the ZA group (OR 0.08,
      95% CI 0.00 to 0.42, p=0.003).
    explanation: >-
      Randomised trial result in SQSTM1 carriers.
  - reference: PMID:38123339
    reference_title: "Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic testing for pathogenic SQSTM1 variants coupled with intervention
      with ZA is well tolerated and has favourable effects on the progression
      of early PDB.
    explanation: >-
      Trial conclusion supporting genetic testing with targeted zoledronic
      acid.
clinical_trials:
- name: ISRCTN11616770
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    ZiPP: genetic testing of relatives of people with Paget disease of bone,
    then a double-blind randomised comparison of a single zoledronic acid
    infusion with placebo in SQSTM1 variant carriers, to prevent the
    development and progression of pagetic lesions.
  target_phenotypes:
  - preferred_term: Paget disease of bone
    term:
      id: HP:0034159
      label: Paget disease of bone
  evidence:
  - reference: ICTRP:ISRCTN11616770
    reference_title: "Zoledronate in the Prevention of Paget's: the ZiPP study"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Scientific title: Randomised trial of genetic testing and targeted
      zoledronic acid therapy to prevent SQSTM1-mediated Paget's disease
    explanation: >-
      WHO ICTRP registration record establishing the trial's identity and its
      SQSTM1 carrier population.
discussions:
- discussion_id: bone_versus_neuromuscular_arm
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Enhanced RANKL-NF-kB Signalling in Osteoclast Precursors
  - pathophysiology#Impaired p62-Mediated Selective Autophagy
  prompt: >-
    Does the bone presentation share the autophagy lesion of the neurological
    and muscle presentations, and what decides which presentation a given
    SQSTM1 carrier develops?
  rationale: >-
    The entry models one shared variant node with two branches: a
    UBA-domain/NF-kB branch for bone and a cargo-receptor/autophagy branch for
    neurons and muscle. The branches are not cleanly separable, since mutant
    osteoclast lineage cells also show autophagy marker changes, and the same
    allele (p.Pro392Leu) produces either or both. Even within bone, two
    knock-in mouse lines disagree on whether the variant alone produces
    lesions or needs a second factor such as measles virus nucleocapsid
    protein; the Paget_Disease_of_Bone entry discusses that viral hypothesis,
    which studies of human pagetic bone have largely failed to confirm.
    Co-inherited variants are a
    partial answer for muscle (TIA1 p.Asn357Ser) and possibly for brain (a
    C9orf72 expansion was found with an SQSTM1 variant in one FTD case), but
    no determinant of the bone versus brain split is known. Coexistence of PDB
    with ALS/FTD may also be under-ascertained, because FTD families were not
    examined for bone disease and PDB families were not assessed for dementia.
  evidence:
  - reference: PMID:27554286
    reference_title: "ALS-FTLD associated mutations of SQSTM1 impact on Keap1-Nrf2 signalling."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Coexistence of PDB and ALS-FTLD is apparently rare and precisely how
      different SQSTM1 mutations (some of which are common to both disorders)
      can lead to either neurodegeneration or PDB is currently unknown
    explanation: >-
      States the open question directly.
  - reference: PMID:26208961
    reference_title: "SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Why some patients develop PDB or ALS and others develop a myopathy is
      unclear, but it may be related to the presence of other inherited
      genetic modifiers.
    explanation: >-
      Proposes genetic modifiers as the source of pleiotropy.
references:
- reference: PMID:20301649
  title: Multisystem Proteinopathy.
  tags:
  - GeneReviews
📚

References & Deep Research

References

1
PMID:20301649
Multisystem Proteinopathy.
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 (1)

Create: SQSTM1-related_Multisystem_Proteinopathy · 2026-10-12T15:37:00Z · View source

New gene-level entry for heterozygous, autosomal dominant SQSTM1 disease (MONDO:0800464), lumped with its three MONDO descendants as has_subtypes rows: PDB3 (MONDO:0008176), FTDALS3 (MONDO:0014640) and DMRV (MONDO:0014945). The ClinGen ALS GCEP curation of SQSTM1 (Moderate, CGGV assertion dae3327f) makes the same lump and splits off the recessive childhood-onset disease, which stays in SQSTM1-Related_Childhood-Onset_Neurodegeneration. PDB3 is also a subtype row of Paget_Disease_of_Bone; it is kept as an ordinary subtype here rather than a curated_in pointer, since no entry curates PDB3 in full. The pathograph has one shared variant node branching into a selective-autophagy arm (LIR/UBA cargo-receptor defect, p62/TDP-43 inclusions, motor neuron, frontotemporal and myofibre degeneration), a KEAP1-NRF2 arm restricted to FTDALS3, a stress-granule node carrying the TIA1 p.Asn357Ser digenic modifier for DMRV, and an osteoclast RANKL/NF-kB arm for PDB3. The contested sufficiency of the P394L knock-in for pagetic lesions is recorded with SUPPORT (PMID:21515589) and REFUTE (PMID:24339057) evidence and a KNOWLEDGE_GAP discussion. Key PMIDs: 11992264, 12374763, 22084127, 24042580, 22972638, 26208961, 29457785, 39142003, 38016875, 27158844, 31362587, 27554286, 24642144, 21515589, 24339057, 38123339 (ZiPP trial), 32176830. One openscientist deep-research report was used: 25/25 references resolved, 0 off topic; term validation needs_review with 6 mislabelled CURIEs, none of which were bound. The report wrongly calls the disease MSP3 with OMIM 616887; MSP4 was used per PMID:26208961 and PMID:36861178. just preflight-dr could not run because the local MONDO build is absent and was not downloaded; a manual check found the report about SQSTM1 throughout (69 SQSTM1 mentions, 4 VCP). Validation: just validate passes with 93/93 snippets verified; entity-ref, causal-target, duplicate-key, enum, snippet, title, gene-activity-grounding and coarse-phenotype gates pass; 20 of 21 phenotypes are causally connected (fracture susceptibility deliberately unconnected because most fractures occur in unaffected bone).

OpenScientist ▸
Key Findings
openscientist-autonomous 25 citations 2026-10-12T15:17:59.747794

Key Findings

Finding 1 — SQSTM1 causes a pleiotropic multisystem proteinopathy spanning IBM, ALS, FTD, and Paget disease of bone

Heterozygous SQSTM1 variants produce a clinical spectrum encompassing inclusion body myopathy (IBM), motor neuron disease/ALS, frontotemporal dementia (FTD), and Paget disease of bone (PDB), unified by shared TDP-43– and p62-positive aggregate pathology and rimmed vacuoles. SQSTM1 is formally designated MSP3 (OMIM 616887), one of a family of MSP genes that also includes VCP, HNRNPA2B1, and HNRNPA1.

As the landmark MSP review states: "Mutations in VCP, HNRNPA2B1, HNRNPA1, and SQSTM1, encoding RNA-binding proteins or proteins in quality-control pathways, cause multisystem proteinopathies (MSP). They share pathological findings of protein aggregation and clinical combinations of inclusion body myopathy (IBM), neurodegeneration [motor neuron disorder (MND)/frontotemporal dementia (FTD)], and Paget disease of bone (PDB)" (PMID: 36861178). In the Mayo Clinic MSP cohort, SQSTM1+TIA1 accounted for 5 of 31 MSP individuals.

Demographically, a Chinese MSP cohort of 953 ALS/IBM/dementia patients identified 29 carriers of MSP-gene variants, with onset predominantly in the 3rd–5th decade and strong male predominance: "Most patients were male (72.4%), with disease onset predominantly in the third to fifth decades of life. The majority of patients (21/29) presented with a single clinical phenotype" (PMID: 41737544). The fact that most patients present with a single phenotype is central to the disease's clinical reality — full multisystem co-occurrence in one individual is the exception, not the rule.

Ontology anchors: MONDO:0800464 (disease); HP:0003198 (Myopathy); HP:0007354 (Amyotrophic lateral sclerosis); HP:0002145 (Frontotemporal dementia); HP:0002661 (Paget disease of bone).

Finding 2 — Pathogenic SQSTM1 variants cluster in the UBA domain and impair selective autophagy with NF-κB activation

In familial PDB, all 14 initially reported SQSTM1 mutations affect the ubiquitin-associated (UBA) domain, with P392L the most prevalent, present in both familial and sporadic cases across populations: "The 14 mutations reported in SQSTM1/p62 all affect the ubiquitin-associated domain of the protein. The P392L mutation is the most commonly observed mutation in PDB patients" (PMID: 17229007).

Functionally, the p62 protein is a multidomain scaffold: it binds ubiquitinated cargo via the UBA domain, LC3 via its LIR motif (acting as a selective autophagy receptor), and sequesters KEAP1 to activate the NFE2L2/Nrf2 antioxidant response. Pathogenic variants disrupt this machinery. Studies of the p.R321C variant demonstrate the dual mechanism: "In vitro studies associated the p62-321C variant with a blockade of autophagy and with the activation of the NF-kB pathway" (PMID: 40374720). A humanized p62-321C mouse developed stimulus-induced seizures, CNS p62/cFos changes, and degenerating spinal motor neurons.

Ontology anchors: GO:0005515 (protein binding); GO:0061136 (regulation of proteasomal protein catabolic process); GO:0000421 (autophagosome membrane); GO:0038061 (NIK/NF-κB signaling). Protein: UniProt Q13501, UBA domain residues ~389–434.

Finding 3 — Biallelic SQSTM1 loss-of-function causes a distinct recessive childhood-onset neurodegeneration (DNECAS)

In sharp mechanistic contrast to the dominant adult disease, biallelic (recessive) loss of p62 produces a childhood/adolescence-onset neurodegenerative disorder. Haack et al. "identified three different biallelic loss-of-function variants in SQSTM1 in nine affected individuals from four families with a childhood- or adolescence-onset neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline" (PMID: 27545679).

Affected fibroblasts showed complete absence of p62 protein and investigators "found evidence of a defect in the early response to mitochondrial depolarization and autophagosome formation" (PMID: 27545679) — directly implicating a mitophagy/autophagy-initiation defect. A novel homozygous frameshift (c.790del) was subsequently reported in childhood-onset progressive neurodegeneration with ataxia and gaze palsy (PMID: 35957775).

Ontology anchors: HP:0001251 (Ataxia); HP:0001332 (Dystonia); HP:0031605 (Vertical gaze palsy); HP:0100543 (Cognitive impairment); GO:0000423 (mitophagy).

Finding 4 — Epidemiology: SQSTM1 is the most common PDB gene; PDB prevalence ~1–2% in older adults but declining, male-predominant, with strong geographic variation

Paget disease of bone, the most frequent SQSTM1-associated phenotype, affects ~1–2% of adults over 55 in high-prevalence regions (UK, Western Europe), with marked geographic clustering (highest in NW England) and a continuing secular decline. In the UK, "the overall standardized incidence decreased from 0.75/10,000 person-years in 1999 to 0.20/10,000 person-years in 2015" (PMID: 33742666).

Prevalence is far lower in Asian populations. In South Korea, researchers reported "a mean prevalence of 1.20 per 100,000 and an age-adjusted incidence ranging from 0.38 to 1.26 per 100,000 person-years" (PMID: 39906256). PDB is male-predominant and strongly age-dependent, with crude incidence rising from ~0.04–0.07/10,000/yr at age 45–49 to 3.7–6.3/10,000/yr at ≥85.

The full SQSTM1-MSP syndrome (neuromuscular + bone) is much rarer than isolated PDB: MSP overall was found in only 3.0% (29/953) of a Chinese ALS/IBM/dementia cohort, and a Japanese nationwide survey ascertained only 47 MSP patients (PMID: 38287512). The secular decline and a rural/livestock (cattle density) association point to an environmental contribution: "A moderately positive correlation (R2 = 0.236) was identified between PDB incidence and the density of female breeding cattle" (PMID: 40408225).

Population / Region Metric Value Source
UK (1999) Standardized incidence 0.75 / 10,000 PY PMID: 33742666
UK (2015) Standardized incidence 0.20 / 10,000 PY PMID: 33742666
South Korea Mean prevalence 1.20 / 100,000 PMID: 39906256
South Korea Age-adjusted incidence 0.38–1.26 / 100,000 PY PMID: 39906256
China (MSP cohort) MSP among ALS/IBM/dementia 29/953 (3.0%) PMID: 41737544
Japan Nationwide MSP patients 47 PMID: 38287512

Finding 5 — Treatment: Zoledronic acid durably controls SQSTM1-associated PDB, and genetic-test-guided prophylaxis can prevent bone lesions

Intravenous zoledronic acid (an aminobisphosphonate; NCIT:C1699) is the mainstay for the bone component. In a long-term retrospective cohort, biochemical response favored treatment strongly: "Primary outcome was more prevalent in the ZOL compared to the NZOL group [42 patients (88%) VS 11 patients (52%) respectively, P = 0.004]" (PMID: 38555314), with sustained normalization of alkaline phosphatase.

Most importantly, the ZiPP/PREVENT-PDB randomized trial of 222 SQSTM1-pathogenic-variant carriers showed that prophylactic zoledronic acid prevented new bone lesions: "Eight of the placebo group had a poor outcome (lesions which were new, unchanged or progressing) compared with none of the ZA group (OR 0.08, 95% CI 0.00 to 0.42, p=0.003)" over a median 84 months (PMID: 38123339). This is a rare example of genotype-guided precision prevention in a Mendelian disease.

The acute phase response (fever, myalgia) after zoledronate can be attenuated by a short course of dexamethasone (PMID: 36970850). By contrast, no disease-modifying therapy exists for the myopathy/ALS/FTD components, which are managed supportively (physiotherapy, occupational therapy, respiratory care).

Ontology anchors: NCIT:C1699 (Zoledronic Acid); NCIT:C1455 (Bisphosphonate); NCIT:C575 (Dexamethasone); CHEBI:46557 (zoledronic acid).

Finding 6 — TIA1/SQSTM1 digenic late-onset distal myopathy defines a homogeneous SQSTM1 muscle phenotype, with SQSTM1 acting as a modifier

The muscle arm of SQSTM1 disease is frequently digenic. Co-inheritance of TIA1 p.Asn357Ser and SQSTM1 p.Pro392Leu produces a strikingly homogeneous phenotype: "These twenty-four patients (75% males) had late-onset (52,6 ± 10,1 years), mainly asymmetric, distal ankle and hand finger extension weakness (75%), mild CK elevation (82.4%) and myopathic EMG" (PMID: 39142003).

The TIA1 allele is enriched in distal myopathy panels and is proposed as a genetic modifier: "We confirm an increased burden of the TIA1 p.Asn357Ser variant in distal myopathy patients which could act as a genetic modifier" (PMID: 39142003). An independent Spanish report confirmed that "a similar phenotype has been attributed to the digenic inheritance of TIA1 c.1070A>G (p.Asn357Ser) and SQSTM1 c.1175C>T (p.Pro392Leu) variants" (PMID: 38016875). Muscle biopsy shows rimmed vacuoles (combined 44–83%) with p62/TDP-43 aggregates. Notably, SQSTM1 can also cause proximal myopathy with rimmed vacuoles via a frameshift variant, broadening the muscle phenotype (PMID: 36998782).

Ontology anchors: HP:0003693 (Distal amyotrophy); HP:0003805 (Rimmed vacuoles); HP:0003236 (Elevated circulating creatine kinase); HP:0003458 (EMG: myopathic abnormalities); HP:0030319 (Finger extensor weakness).

Finding 7 — Mutant p62 potentiates RANK-induced NF-κB activation and osteoclastogenesis (bone arm) and accelerates ALS progression (neuro arm)

On the bone side, PDB-associated p62 mutants act by gain-of-function on NF-κB: "p62 mutants increased NF-kappaB activation and significantly potentiated osteoclast formation and bone resorption in human primary cell cultures" (PMID: 16813535). This study described a novel K378X truncation causing a severe polyostotic phenotype alongside P392L and E396X.

On the neurodegeneration side, SQSTM1 missense variants span the PB1, TRAF6-binding, PEST, and UBA domains and worsen prognosis. In a Chinese ALS cohort, "the ΔFS analysis revealed that the risk of death or tracheostomy was significantly increased in SQSTM1 mutation carriers (p < 0.05)" (PMID: 25708934). Neuropathologically, p62 immunohistochemistry reliably labels TDP-43–positive and C9RANT-positive neuronal cytoplasmic inclusions in FTLD/ALS tissue.

Ontology anchors: GO:0038061 (NIK/NF-κB signaling); GO:0045670 (regulation of osteoclast differentiation); CL:0000092 (osteoclast); CL:0000100 (motor neuron).

Finding 8 — Diagnostic workup is organ-specific

Diagnosis depends on which arm is manifest:

  • Bone arm (PDB): Usually detected incidentally via isolated elevated serum total/bone alkaline phosphatase (elevated in ~90% of PDB; LOINC 6768-6) or on radiographs. "Most cases of PDB are diagnosed incidentally on radiographs or as an isolated elevation of serum alkaline phosphatase... Diagnosis is made on the basis of typical radiological features on plain films, while a radionuclide bone scan may be used to assess the extent of disease" (PMID: 33543158). Pathognomonic radiographic features include cortical thickening, medullary expansion, osteolytic "blade of grass" fronts, and mixed lytic-sclerotic skull; histology shows mosaic cement lines. Bone-turnover markers (CTX, P1NP) are elevated.
  • Neuromuscular arm: Requires needle EMG (myopathic ± neurogenic), muscle MRI (distal fatty replacement, e.g., medial gastrocnemius), and muscle biopsy: "Muscle biopsy showed rimmed vacuoles (44.4%), myofibrillar disorganization (16.7%) or both (38.9%), with P62/TDP43 aggregates" (PMID: 39142003).
  • Definitive diagnosis is molecular: Targeted SQSTM1 sequencing or multigene MSP/ALS/distal-myopathy NGS panels (including TIA1), with WES/WGS for atypical cases.

Ontology anchors: LOINC 6768-6 (Alkaline phosphatase); NCIT:C17007 (genetic testing); HP:0003236 (elevated CK).

Finding 9 — Mouse models show p62 P394L (= human P392L) causes osteoclast RANKL-hyperresponsiveness but requires a second hit for full Paget lesions

The gene-environment nature of the bone arm is directly demonstrated in mice. "We generated p62(P394L) knock-in mice (p62KI) and found that although OCL numbers were increased, the mice did not develop pagetic lesions. However, mice expressing both MVNP and p62KI developed more exuberant pagetic lesions than mice expressing MVNP alone" (PMID: 24339057). The downstream mediator is IL-6: "Interleukin-6 (IL-6) production is essential for the pagetic phenotype, because transgenic mice with MVNP targeted to OCLs develop pagetic OCLs and lesions, but this phenotype is absent when MVNP mice are bred to IL-6(-/-) mice" (PMID: 24339057).

This explains incomplete, age-dependent penetrance of PDB: the p62 UBA mutation primes osteoclasts to RANKL but, alone, is insufficient; a paramyxoviral/inflammatory "second hit" acting through IL-6 is needed for full lesions. Available model systems therefore include: p62(P394L) knock-in mice (bone), the humanized p62-R321C mouse (CNS: seizures, motor-neuron degeneration; PMID: 40374720), Sqstm1/p62-null mice (mitophagy defect; models the biallelic human phenotype), and patient fibroblasts/iPSC and RAW264.7 osteoclast cultures.

Ontology anchors: NCBI Taxon 10090 (Mus musculus); MGI Sqstm1; CL:0000092 (osteoclast); GO:0032635 (interleukin-6 production).

Finding 10 — Prognosis is organ-specific: PDB arm usually benign/treatable but <1% undergo osteosarcoma transformation; neuro arm is progressive and life-limiting

Most SQSTM1-associated PDB is mild and monostotic (77% monostotic; only 3% fracture in one cohort) and controllable with bisphosphonates. Complications include bone pain, deformity, fractures, deafness (skull involvement), compression neuropathy/spinal cord compromise, secondary osteoarthritis, and high-output cardiac states.

The gravest bone complication is malignant transformation: "Neoplastic transformation is a rare but serious complication of Paget's disease of bone (PDB), occurring in fewer than 1% of individuals with polyostotic disease. Their prognosis is poor, with less than 50% surviving 5 years" (PMID: 32106343). Spinal pagetic osteosarcoma has a 5-year survival as low as 10% (PMID: 42359209). Transformation is associated with a germline ZNF687 P937R founder mutation and dual SQSTM1+ZNF687 genotypes — a case report documented "genetic testing confirming dual SQSTM1 and ZNF687 mutations" (PMID: 41630218).

In contrast, the neuromuscular components are relentlessly progressive: distal myopathy causes slowly progressive disability over 10+ years; SQSTM1-ALS carriers have accelerated decline and shortened survival (PMID: 25708934); FTD and the biallelic childhood neurodegeneration are progressive and fatal.

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

Shared initiating lesion: 1. A germline SQSTM1 variant (most commonly a UBA-domain missense, e.g., p.P392L) alters p62 function → impairs ubiquitin-cargo binding and p62's dual role as autophagy receptor and signaling scaffold (PMID: 17229007).

The pathway then branches according to cell type, gene dose (mono- vs biallelic), and environment:

BRANCH A — Bone (gain-of-function, environment-gated): 2A. Mutant p62 potentiates RANK→NF-κB signaling in osteoclast precursors (PMID: 16813535) → leads to osteoclast RANKL-hyperresponsiveness and increased osteoclast number. 3A. Alone this is insufficient (p62KI mice do not develop lesions) → a second hit (paramyxoviral MVNP; inferred from epidemiologic measles/livestock associations) acts via IL-6 (PMID: 24339057) → results in exuberant, disorganized bone remodeling. 4A. Leads to focal accelerated bone turnover → cortical thickening, medullary expansion, deformity, fractures, deafness → clinical Paget disease of bone. 5A. Rarely (<1%, often with a ZNF687 second hit) → malignant transformation to osteosarcoma (PMID: 32106343).

BRANCH B — Neuromuscular (loss-of-function / impaired autophagy): 2B. Mutant p62 blocks selective autophagy and impairs mitophagy (PMID: 40374720) → leads to accumulation of ubiquitinated cargo and damaged mitochondria. 3B. Results in cytoplasmic TDP-43 and p62 aggregation with rimmed vacuoles in myofibers and neurons (PMID: 39142003). 4B. Co-modifier alleles (e.g., TIA1 p.N357Ser) lower the threshold → digenic distal myopathy (PMID: 39142003); in motor/cortical neurons → ALS/FTD with accelerated progression (PMID: 25708934).

BRANCH C — Recessive childhood neurodegeneration (complete loss-of-function): 2C. Biallelic LoF → complete absence of p62 protein → defective early mitophagy response (PMID: 27545679) → leads to childhood-onset neurodegeneration with ataxia, dystonia, gaze palsy (DNECAS).

Branch comparison table

Feature Bone arm (PDB) Neuromuscular arm (IBM/ALS/FTD) Recessive childhood (DNECAS)
Inheritance Autosomal dominant Autosomal dominant (± digenic) Autosomal recessive
Dominant mechanism Gain-of-function (NF-κB↑) Loss-of-function (autophagy↓) Complete LoF (no p62)
Variant type UBA missense (P392L) Missense across domains; truncating Biallelic truncating/frameshift
Second hit needed Yes (MVNP/IL-6) Modifier alleles (TIA1) No
Onset Older adult (>55) 3rd–5th decade Childhood/adolescence
Penetrance Incomplete, age-dependent Incomplete, variable High (recessive)
Pathology Mosaic cement lines, osteoclast↑ p62/TDP-43 aggregates, rimmed vacuoles Mitophagy defect
Prognosis Benign, treatable Progressive, life-limiting Progressive, fatal
Therapy Zoledronic acid (preventable!) Supportive only Supportive only

ASCII schematic

 SQSTM1 / p62 germline variant
 (UBA domain, e.g. P392L)
            |
+-------------------+--------------------+
|                                        |
  GAIN-OF-FUNCTION                        LOSS-OF-FUNCTION
  (RANK -> NF-kB up)                      (autophagy/mitophagy down)
|                                        |
  osteoclast hyper-                      ubiquitin + damaged
  responsiveness                         mitochondria accumulate
|                                        |
  + MVNP / IL-6  <-- environmental        p62/TDP-43 aggregation
    SECOND HIT        trigger                    |
|                             +----------+-----------+
  Paget disease of bone               |                      |
|                        +TIA1 modifier         biallelic LoF
  <1% osteosarcoma               (digenic)                   |
  (+ZNF687)                           |                 childhood
              distal myopathy /          neurodegeneration
              IBM / ALS / FTD            (ataxia, gaze palsy)

Evidence Base

PMID Title (abbreviated) Supports finding(s) Evidence type
36861178 MSPs and MSP-like disorders: spectrum F1 (disease definition) Human clinical / review
41737544 Chinese MSP genetic spectrum F1, F4 (demographics) Human clinical cohort
17229007 SQSTM1 mutation frequencies/haplotypes F2 (UBA clustering, P392L) Human genetics
40374720 p.R321C CNS abnormalities F2 (autophagy/NF-κB), F9 (mouse) In vitro + mouse
27545679 Biallelic SQSTM1 childhood neurodegeneration F3 (DNECAS) Human genetics + fibroblasts
35957775 Novel c.790del recessive case F3 Human case
33742666 UK PDB declining incidence F4 (epidemiology) Epidemiology
39906256 South Korea PDB epidemiology F4 Epidemiology
40408225 PDB decline & livestock association F4 (environment) Epidemiology
38287512 Japan nationwide MSP survey F4 Epidemiology
38555314 Zoledronic acid long-term effectiveness F5 (treatment) Clinical cohort
38123339 ZiPP/PREVENT-PDB RCT (genotype-guided) F5 (prevention) Randomized trial
36970850 Dexamethasone for zoledronate APR F5 (adverse-event mgmt) Randomized trial
39142003 TIA1/SQSTM1 digenic myopathy landscape F6, F8 (diagnosis) Human clinical cohort
38016875 Digenic TIA1/SQSTM1 Spanish patients F6 Human case series
36998782 Frameshift SQSTM1 proximal MRV F6 Human case
16813535 K378X, NF-κB, osteoclastogenesis F7 (bone mechanism) In vitro functional
25708934 Six SQSTM1 mutations in Chinese ALS F7, F10 (prognosis) Human genetics
33543158 Paget's disease clinical update F8 (diagnosis) Clinical review
24339057 IL-6/MVNP + p62 P394L knock-in mice F9 (GxE, model) Mouse model
32106343 ZNF687 in neoplastic PDB transformation F10 (prognosis) Human genetics
41630218 Spinal PDB malignant transformation F10 Human case
42359209 Pagetic spinal osteosarcoma review F10 Clinical review

Challenges / nuances: The VCP-focused MSP therapeutic literature (rapamycin/chloroquine, exercise training; e.g. PMID: 24130765) is encouraging for the autophagy-targeting concept but is not SQSTM1-specific, and one key paper was retracted (PMID: 25884947) — it should not be over-extrapolated to SQSTM1. The livestock/measles environmental link is correlational (R²=0.236) and mechanistically supported only in mice, not proven in human SQSTM1 carriers.

Section-by-Section Knowledge-Base Content

1. Disease Information. Adult-onset dominant multisystem proteinopathy (MSP3, OMIM 616887, MONDO:0800464) plus a distinct recessive pediatric neurodegeneration (DNECAS). Synonyms: SQSTM1-related MSP; p62-related myopathy/ALS/FTD/PDB. Information is aggregated from case series, cohorts, and registries (disease-level), not single-patient EHR.

2. Etiology. Primary cause: germline SQSTM1 variants. Genetic risk: UBA-domain missense (P392L most common); modifier TIA1 p.N357Ser (muscle), ZNF687 P937R (malignant transformation). Environmental: paramyxovirus (measles/MVNP), rural/cattle exposure, age, male sex. Gene-environment interaction is proven in mice (p62KI requires MVNP/IL-6; PMID: 24339057).

3. Phenotypes. PDB (HP:0002661), distal amyotrophy (HP:0003693), rimmed vacuoles (HP:0003805), elevated CK (HP:0003236), ALS (HP:0007354), FTD (HP:0002145), ataxia (HP:0001251), dystonia (HP:0001332), gaze palsy (HP:0031605), hearing loss (HP:0000365), cognitive decline (HP:0100543). Onset mostly 3rd–5th decade (neuromuscular) or >55 (bone); childhood for recessive form. Progressive for neuro arm; treatable/stable for bone.

4. Genetic/Molecular. SQSTM1 (HGNC:11280, chr5q35, UniProt Q13501). Variants: missense, nonsense (K378X, E396X), frameshift. Classification per ACMG; P392L pathogenic. Modifier genes: TIA1, ZNF687. Rare in gnomAD. Germline origin. Functional consequence: gain-of-function (NF-κB/bone) and loss-of-function (autophagy/neuro).

5. Environmental. Paramyxovirus/measles nucleocapsid (via IL-6), livestock/rural exposure; secular decline implies modifiable environmental component.

6. Mechanism. See causal chain above. Pathways: RANK–NF-κB (KEGG), selective autophagy/mitophagy (GO:0000423), KEAP1-NFE2L2. Cell types: osteoclast (CL:0000092), motor neuron (CL:0000100), skeletal myofiber.

7. Anatomy. Bone (UBERON:0001474; skull, spine, pelvis, long bones), skeletal muscle (UBERON:0001134; distal > proximal), spinal cord/motor neurons, frontotemporal cortex, cerebellum. Subcellular: autophagosome (GO:0005776), lysosome, mitochondrion.

8. Temporal. Adult/late onset (bone, >55; neuromuscular, 3rd–5th decade), childhood for recessive. Insidious, chronic, progressive (neuro) vs. focal/stable (bone).

9. Inheritance/Population. AD (dominant arms), AR (DNECAS), often digenic. Incomplete, age-dependent penetrance. Variable expressivity. PDB ~1–2% in high-prevalence regions, declining; male-predominant; NW England clustering.

10. Diagnostics. ALP + bone-turnover markers + radiography/bone scan (bone); EMG + muscle MRI + biopsy with p62/TDP-43 (muscle); molecular SQSTM1 sequencing / NGS panels (definitive).

11. Prognosis. Bone arm benign/treatable, <1% osteosarcoma (poor, <50% 5-yr survival). Neuro arm progressive, life-limiting; ALS carriers have shortened survival.

12. Treatment. Zoledronic acid (NCIT:C1699) for PDB — including genotype-guided prophylaxis; dexamethasone for APR; supportive care (PT/OT, respiratory) for neuromuscular arms. No disease-modifying neuro therapy.

13. Prevention. Primary/secondary: genetic testing + prophylactic zoledronic acid in SQSTM1 carriers (proven in ZiPP RCT); genetic counseling; cascade testing. Tertiary: bisphosphonates to prevent deformity/complications.

14. Other species. Mouse (NCBI Taxon 10090) ortholog Sqstm1; p62(P394L) knock-in and p62-null models. No major naturally occurring animal disease documented.

15. Model organisms. p62(P394L) knock-in (bone), humanized p62-R321C (CNS), Sqstm1-null (mitophagy/recessive), patient fibroblasts/iPSC, RAW264.7 osteoclast cultures.

Limitations and Knowledge Gaps

  1. No dedicated SQSTM1-MSP primary dataset was analyzed — this report synthesizes published literature; all statistics are extracted from cited studies.
  2. Penetrance and genotype-phenotype rules are imprecise. Why one carrier develops PDB, another ALS, and another nothing is unexplained beyond modifier alleles and environmental hits.
  3. The environmental "second hit" is proven only in mice. The measles/MVNP-IL-6 axis and livestock correlation (R²=0.236) are not mechanistically confirmed in human SQSTM1 carriers.
  4. No disease-modifying therapy for the neuromuscular arms. Autophagy-modulating strategies remain extrapolations from VCP models (one key paper retracted).
  5. Cohorts are small and geographically skewed (Europe, East Asia); carrier frequency, incidence of the full MSP syndrome, and sex ratios for the neuromuscular arms are poorly quantified.
  6. Prognostic biomarkers are lacking for predicting which carriers will convert to neurodegeneration.

Proposed Follow-up Experiments / Actions

  1. Genotype-phenotype registry: Pool international SQSTM1 carriers to estimate arm-specific penetrance, modifier burden (TIA1, ZNF687), and environmental covariates.
  2. Test the viral second-hit hypothesis in humans: Serological/PCR studies for paramyxovirus exposure stratified by SQSTM1 genotype and PDB status.
  3. iPSC-derived osteoclast + motor-neuron isogenic panels carrying P392L, R321C, and biallelic LoF to dissect the gain- vs loss-of-function branch point quantitatively.
  4. Biomarker discovery: Longitudinal serum/CSF neurofilament, TDP-43, and bone-turnover markers to predict neuromuscular conversion in asymptomatic carriers.
  5. Therapeutic trials of autophagy enhancers specifically in SQSTM1 muscle/neuron models before clinical translation.
  6. Extend prophylaxis evidence: Longer-term ZiPP follow-up and health-economic analysis to inform guidelines on genotype-guided zoledronic acid.
  7. Screen for ZNF687 co-mutation in polyostotic SQSTM1-PDB patients as a malignant-transformation risk stratifier.

Report compiled from 10 confirmed findings across 5 investigation iterations and 60 reviewed papers. Evidence types span human clinical cohorts, human genetics, in vitro functional assays, mouse models, and epidemiology.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 25
Resolved 25
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 25
On topic 16
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 33
Resolved 32
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 28
Terms named correctly 19
Terms named as a different term 6
Terms whose name is worth a second look 3

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:0800464 (3 mentions) - the report calls it "disease"; MONDO calls it SQSTM1-related multisystem proteinopathy
  • HP:0002661 (2 mentions) - the report calls it "Paget disease of bone"; HP calls it Painless fractures due to injury
  • HP:0031605 (2 mentions) - the report calls it "Vertical gaze palsy"; HP calls it Abnormal fundus pigmentation
  • NCIT:C1455 (1 mention) - the report calls it "Bisphosphonate"; NCIT calls it Conjugate Vaccine
  • NCIT:C575 (1 mention) - the report calls it "Dexamethasone"; NCIT calls it Immunotoxin
  • NCIT:C17007 (1 mention) - the report calls it "genetic testing"; NCIT calls it Positron Emission Tomography

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:

  • GO:0038061 (2 mentions) - the report calls it "NIK/NF-κB signaling"; GO calls it non-canonical NF-kappaB signal transduction, and lists "NIK/NF-kappaB signaling" among its other names
  • HP:0003236 (3 mentions) - the report calls it "Elevated circulating creatine kinase", "elevated CK"; HP calls it Elevated circulating creatine kinase activity, and lists "Elevated serum CPK" among its other names
  • HP:0030319 (1 mention) - the report calls it "Finger extensor weakness"; HP calls it Weakness of facial musculature, and lists "Face weakness" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • HP:0003236 - called "Elevated circulating creatine kinase", "elevated CK"