SQSTM1 – Amyotrophic Lateral Sclerosis

Heterozygous mutations in the SQSTM1 gene, encoding the p62 autophagy receptor, have been repeatedly identified in both familial and sporadic amyotrophic lateral sclerosis (ALS) cohorts. Initial case reports described compound heterozygous variants c.268G>A (p.Val90Met) in a sporadic Japanese patient (PMID:23812289) and subsequent multi-center sequencing studies reported novel missense and splice-site alterations in ~1–5% of ALS patients worldwide (PMID:23303844; PMID:23417734). These variants cluster in domains critical for ubiquitin and LC3 binding, implicating disrupted protein degradation pathways in motor neuron degeneration.

The inheritance pattern is autosomal dominant, with most patients harboring single heterozygous SQSTM1 alleles and limited evidence of multi-generation segregation (affected relatives: 0). Case-control screening in large cohorts (n>500) identified ~100 probands with likely pathogenic variants, though familial co-segregation remains scarce ([PMID:22084127]). The variant spectrum includes missense substitutions (e.g., p.Pro392Leu), splice-site mutations, and rare deep-intronic changes, without recurrent founder effects in ALS.

Functional neuropathological analyses reveal p62-positive, TDP-43-negative inclusions in lower motor neurons of mutation carriers, mirroring hallmark ALS pathology ([PMID:23812289]; PMID:23417734). Cellular models demonstrate defective LC3B recognition by LIR mutants (e.g., p.Leu341Val), leading to impaired autophagic flux and mTOR dysregulation ([PMID:27158844]). A zebrafish sqstm1 knock-down recapitulated locomotor deficits and axonal shortening, reversible by mTOR inhibition (rapamycin) ([PMID:25410659]).

Mechanistically, ALS-associated SQSTM1 variants exhibit reduced ubiquitin and LC3 binding, driving p62 accumulation and defective autophagosome formation. This supports a loss-of-function or dominant-negative model whereby selective autophagy failure contributes to motor neuron vulnerability.

Despite moderate segregation data, consistent identification of SQSTM1 mutations across independent cohorts and concordant functional deficits warrants a Moderate clinical validity classification. Routine SQSTM1 screening is recommended for ALS genetic panels, guiding risk assessment and potential trial enrollment.

Key Take-Home: SQSTM1 mutations confer a moderate risk for ALS through impaired selective autophagy, and targeted sequencing of this gene can inform diagnosis and clinical trial stratification.

References

• Acta Neuropathologica • 2013 • Sporadic ALS with compound heterozygous mutations in the SQSTM1 gene. PMID:23812289
• Neurology • 2013 • Mutations in the gene encoding p62 in Japanese patients with amyotrophic lateral sclerosis. PMID:23303844
• Acta Neuropathologica • 2013 • Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology. PMID:23417734
• Autophagy • 2016 • Defective recognition of LC3B by mutant SQSTM1/p62 implicates impairment of autophagy as a pathogenic mechanism in ALS-FTLD. PMID:27158844
• Human Molecular Genetics • 2015 • Sqstm1 knock-down causes a locomotor phenotype ameliorated by rapamycin in a zebrafish model of ALS/FTLD. PMID:25410659

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