SQSTM1

Chr 5ADAR

sequestosome 1

Also known as: A170, DMRV, EBIAP, FTDALS3, NADGP, OSIL, PDB3, ZIP3

NCBI Gene: 8878 ENSG00000161011 UniProt: Q13501 OMIM: 601530

This gene encodes a multifunctional scaffolding protein that binds ubiquitin, regulates NF-kB signaling pathway activation, and functions in autophagy. Mutations cause autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis, distal myopathy with rimmed vacuoles, and Paget disease of bone, as well as autosomal recessive childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy. The pathogenic mechanism involves disrupted protein aggregation clearance and impaired autophagy processes.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Frontotemporal dementia and/or amyotrophic lateral sclerosis 3MIM #616437

Myopathy, distal, with rimmed vacuolesMIM #617158

Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onsetMIM #617145

Paget disease of bone 3MIM #167250

Clinical highlights

Gene-disease validity (ClinGen)

frontotemporal dementia and/or amyotrophic lateral sclerosis 3 · ADModerateconsider for supplementary testing

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

750

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.80

LOEUF

LOF

Mechanism· G2P

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