SS18L1 – Amyotrophic Lateral Sclerosis

Heterozygous variants in SS18L1 have been reported in four unrelated ALS probands across a trio-based and familial cohort ([PMID:24360741]). A de novo nonsense variant Q388Ter deleting the last nine amino acids was identified in one sporadic trio, and a missense variant c.369T>G (p.Ileu123Met) was found in one of 62 familial ALS cases; two additional heterozygous alleles—c.660_668del (p.Gln222_Ser224del) and c.790G>A (p.Ala264Thr)—were each observed in single FALS patients and absent from 180 controls and population databases ([PMID:24360741]). No segregation beyond the proband was reported, and replication cohorts remain limited. Overall, genetic data reach a Limited level of clinical validity based on ClinGen criteria.

Functional studies using CREST (SS18L1) knockout and Q394X knock-in mice recapitulate key ALS-like features including motor coordination deficits, microglial activation, and reduced activity-dependent dendritic outgrowth, supporting a loss-of-function mechanism ([PMID:30976389]). CREST haploinsufficiency and the human‐analogous Q388X allele in mice lead to upregulated neuronal pro-inflammatory cytokines (Ccl2, Cxcl10) via histone deacetylation deficits, further linking SS18L1 dysfunction to neuroinflammatory pathways. These concordant in vivo data provide Moderate functional evidence but require further validation in human tissues.

References

• Neurobiology of aging • 2014 • Genetic analysis of SS18L1 in French amyotrophic lateral sclerosis. PMID:24360741
• Translational neurodegeneration • 2019 • Loss of CREST leads to neuroinflammatory responses and ALS-like motor defects in mice. PMID:30976389

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