SQSTM1
protein-codingsequestosome 1, the group of Zinc fingers ZZ-type
Gene summary
This gene encodes a multifunctional protein that binds ubiquitin and regulates activation of the nuclear factor kappa-B (NF-kB) signaling pathway. The protein functions as a scaffolding/adaptor protein in concert with TNF receptor-associated factor 6 to mediate activation of NF-kB in response to upstream signals. Alternatively spliced transcript variants encoding either the same or different isoforms have been identified for this gene. Mutations in this gene result in sporadic and familial Paget disease of bone. [provided by RefSeq, Mar 2009]
- PDB3
- OSIL
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~31.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014940
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0014640
Submitter: ClinGen
*SQSTM1* was first reported in relation to autosomal dominant frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) 3 (OMIM: 616437) in 2011 (Fecto et al., PMID: 22084127). *SQSTM1* encodes Sequestosome 1 (sqstm1/p62) and is a scaffolding protein that regulates multiple biological processes, including NFKB1 signaling, apoptosis, transcription regulation, ubiquitin-mediated autophagy. *SQSTM1* has also been associated with autosomal dominant distal myopathy/myositis (OMIM: 617158), autosomal dominant Paget disease of bone 3 (OMIM: 167250), and autosomal recessive, childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy (OMIM: 617145). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, 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. However, we found a difference in molecular mechanism, inheritance pattern, and phenotypic variability between childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy and FTD/ALS 3, and these disease entities were split. This split curation for autosomal recessive, childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy will be curated separately. The association between *SQSTM1* and ALS was first established in an aggregate variant case-control analysis that identified an association between non-synonymous rare variants in the gene and ALS based on the Sanger sequencing of *SQSTM1* in 1092 ALS cases and 1448 controls (Fecto et al., PMID: 22084127). This curation also includes one other case-control analysis from 1 publication that was scored (PMIDs: 24899140). Additionally, 28 variants, including missense, nonsense, and splicing variants, reported in 28 probands from 14 publications were scored in this curation. Based on the curation, a genetic evidence score of 5.6 was reached. The majority of variants identified in *SQSTM1* appear to be missense variants. The gene-disease association is also supported by experimental evidence describing physical interaction with other known ALS associated genes (PMIDs: 30022074, 30290707, and 19765191); aberrant expression in patient cells (PMID: 14762676); functional alterations in patient and non-patient cells (PMIDs: 31362587, 28490746, 27554286, and 27158844); and establishment of model organisms and rescues (PMIDs: 33557921 and 25410659). An experimental evidence score of 5.5 was reached. Although the final score of 11.1 is typically rounded to the next highest whole number based on SOPv9, the ALS GCEP has chosen to apply standard rounding guidelines resulting in a score of 11 and a classification of moderate association with FTD/ALS 3. Notably, the current literature lacks evidence of variant segregation in *SQSTM1* , which is needed to gain a greater understanding of the involvement of *SQSTM1* in ALS. It is important to understand that in the clinical diagnostic setting, the identification of missense variants of uncertain significance will be common in this gene, and variant interpretation must be completed with caution. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.This classification was approved by the ClinGen ALS GCEP on the meeting date Decemeber 13, 2022 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0014940
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014940
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0009807
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0008176
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0014640
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0004976
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0017161
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0017160
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008176
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014640
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014940
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008176
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Musculoskeletal; Neurologic; Oncologic
Intervention: Musculoskeletal; Oncologic
Rationale: Medical management (eg, inhibitors of osteoclastic bone resorption) can be beneficial - bisphosphonates are the current first line of treatment; Awareness of the risk of related oncologic processes (eg, osteosarcoma) may be beneficial to allow early treatment
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SQSTM1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003900.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 6 | 185 | 4 | 195 | ||
| missense | 3 | 5 | 393 | 22 | 1 | 424 |
| nonsense | 13 | 2 | 2 | 17 | ||
| start loss | 1 | 1 | 2 | 4 | ||
| frameshift | 19 | 13 | 4 | 36 | ||
| splice donor/acceptor (+/-2bp) | 2 | 9 | 7 | 18 | ||
| Total | 38 | 30 | 414 | 207 | 5 | 694 |
Highest pathogenic variant AF is 0.0014211744
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003891.1 | 8 | MANE Select | |
| Ensembl | ENSP00000374455.4 | 8 | MANE Select | |
| RefSeq | NP_001135770.1 | 7 | Standard | |
| RefSeq | NP_001135771.1 | 7 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| sqstm1 | Danio rerio | Structure: motor neuron Quality: decreased branchiness abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Mitophagy - animal - Homo sapiens (human)
- Necroptosis - Homo sapiens (human)
- Fluid shear stress and atherosclerosis - Homo sapiens (human)
- Osteoclast differentiation - Homo sapiens (human)
- Cellular senescence - Homo sapiens (human)
Biological Process
- negative regulation of transcription by RNA polymerase II
- autophagy of mitochondrion
- mitophagy
- positive regulation of protein phosphorylation
- immune system process
Molecular Function
- protein serine/threonine kinase activity
- protein kinase C binding
- protein binding
- zinc ion binding
- enzyme binding
Cellular Component
- phagophore assembly site
- P-body
- nucleoplasm
- cytoplasm
- mitochondrion
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000389805
- Coding exons
- 8
- Length
- 31691
- Individuals with no LoFs
- 125727
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 21
- Defined
- 125748
- p
- 0.0000835
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.940 | 304 | 261 | 1.16 | 0.0000174 | 2843 |
| Missense (PolyPhen) | 72 | 65.532 | 1.0987 | 725 | ||
| Synonymous | -2.24 | 138 | 108 | 1.27 | 0.00000783 | 872 |
| Loss of Function | 2.18 | 8 | 18.0 | 0.445 | 8.68e-7 | 215 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000097 | 0.000097 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Autophagy receptor required for selective macroautophagy (aggrephagy). Functions as a bridge between polyubiquitinated cargo and autophagosomes. Interacts directly with both the cargo to become degraded and an autophagy modifier of the MAP1 LC3 family (PubMed:16286508, PubMed:20168092, PubMed:24128730, PubMed:28404643, PubMed:22622177). Along with WDFY3, involved in the formation and autophagic degradation of cytoplasmic ubiquitin- containing inclusions (p62 bodies, ALIS/aggresome-like induced structures). Along with WDFY3, required to recruit ubiquitinated proteins to PML bodies in the nucleus (PubMed:24128730, PubMed:20168092). May regulate the activation of NFKB1 by TNF- alpha, nerve growth factor (NGF) and interleukin-1. May play a role in titin/TTN downstream signaling in muscle cells. May regulate signaling cascades through ubiquitination. Adapter that mediates the interaction between TRAF6 and CYLD (By similarity). May be involved in cell differentiation, apoptosis, immune response and regulation of K(+) channels. Involved in endosome organization by retaining vesicles in the perinuclear cloud: following ubiquitination by RNF26, attracts specific vesicle- associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport (PubMed:27368102). {ECO:0000250|UniProtKB:O08623, ECO:0000250|UniProtKB:Q64337, ECO:0000269|PubMed:10356400, ECO:0000269|PubMed:10747026, ECO:0000269|PubMed:11244088, ECO:0000269|PubMed:12471037, ECO:0000269|PubMed:15340068, ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:15911346, ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:16079148, ECO:0000269|PubMed:16286508, ECO:0000269|PubMed:19931284, ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:22622177, ECO:0000269|PubMed:24128730, ECO:0000269|PubMed:27368102, ECO:0000269|PubMed:28404643}.;
- Disease
- DISEASE: Paget disease of bone 3 (PDB3) [MIM:167250]: A disorder of bone remodeling characterized by increased bone turnover affecting one or more sites throughout the skeleton, primarily the axial skeleton. Osteoclastic overactivity followed by compensatory osteoblastic activity leads to a structurally disorganized mosaic of bone (woven bone), which is mechanically weaker, larger, less compact, more vascular, and more susceptible to fracture than normal adult lamellar bone. {ECO:0000269|PubMed:11992264, ECO:0000269|PubMed:12374763, ECO:0000269|PubMed:14584883, ECO:0000269|PubMed:15125799, ECO:0000269|PubMed:15146436, ECO:0000269|PubMed:15176995, ECO:0000269|PubMed:15207768, ECO:0000269|PubMed:19931284}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=In a cell model for Huntington disease (HD), appears to form a shell surrounding aggregates of mutant HTT that may protect cells from apoptosis, possibly by recruiting autophagosomal components to the polyubiquitinated protein aggregates. {ECO:0000269|PubMed:16286508}.; DISEASE: Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (FTDALS3) [MIM:616437]: A neurodegenerative disorder characterized by frontotemporal dementia and/or amyotrophic lateral sclerosis in affected individuals. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. Some FTDALS3 patients may also develop Paget disease of bone. {ECO:0000269|PubMed:22084127, ECO:0000269|PubMed:24042580, ECO:0000269|PubMed:24899140, ECO:0000269|PubMed:25114083}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset (NADGP) [MIM:617145]: A neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline. Disease onset is in childhood or adolescence. NADGP transmission pattern is consistent with autosomal recessive inheritance. {ECO:0000269|PubMed:27545679}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myopathy, distal, with rimmed vacuoles (DMRV) [MIM:617158]: An autosomal dominant myopathy with adult onset, characterized by muscle weakness of the distal upper and lower limbs, walking difficulties, and proximal weakness of the shoulder girdle muscles. Muscle biopsy shows rimmed vacuoles. {ECO:0000269|PubMed:26208961}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.237
Intolerance Scores
- LoFtool
- 0.0328
- RVIS EVS
- -0.26
- RVIS percentile EVS
- 34.88
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.834
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |