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This summary consolidates evidence linking rare hypermorphic variants of SARM1 (HGNC:17074) with amyotrophic lateral sclerosis (MONDO_0004976). Multiple independent studies demonstrate that several SARM1 alleles exhibit constitutive NADase activity, with one study reporting that 12 out of 42 rare variants identified in over 8500 ALS patients confer a gain‑of‑function effect (PMID:34991663, PMID:34796871). These findings provide robust evidence for a strong gene‑disease association that is supported by both genetic and experimental data.
Genetic evidence is primarily based on the identification of patient‑specific missense and in‑frame microdeletion variants which disrupt SARM1 autoinhibition. A representative variant, reported as c.550G>A (p.Val184Gly), exemplifies the type of coding change that leads to continuous, unregulated NADase activity. Although detailed familial segregation data is not available, the consistent observation of these variants in unrelated probands adds significant weight to their pathogenicity (PMID:34796871).
Functional studies have established that aberrant SARM1 activity is directly linked to neurodegeneration. In vitro experiments in cultured dorsal root ganglion neurons and in vivo mouse models demonstrate that constitutively active SARM1 variants trigger axonal loss, motor dysfunction, and sustained neuroinflammation, thereby recapitulating key features of ALS (PMID:34991663).
Structural investigations further support the pathogenic model by revealing that SARM1 assembles into an octameric ring structure, a configuration essential for its enzymatic activation. This insight into the molecular architecture of SARM1 enhances our understanding of how specific variants may destabilize the auto‑inhibited state and drive disease (PMID:31278906).
Additional functional evidence indicates that the NAD+ hydrolase activity of SARM1 plays a dual role in both degenerative and developmental contexts. Studies using model organisms demonstrate that increased NADase activity correlates with neurodegenerative outcomes, reinforcing the proposed mechanism of disease (PMID:35737728).
Interestingly, while the predominant findings support a damaging gain‑of‑function effect, some reports have identified natural SARM1 loss‑of‑function variants that might confer protection, suggesting a nuanced spectrum of variant effects within the gene (PMID:35974060).
Overall, the integration of genetic and experimental evidence firmly supports a strong association between SARM1 and ALS. The convergence of variant enrichment studies, functional assays, and structural analysis not only advances diagnostic decision‑making and commercial application but also lays a compelling foundation for future research and publication.
Key Take‑home Sentence: Rare gain‑of‑function SARM1 variants contribute to ALS pathogenesis by unleashing constitutive NADase activity that drives neurodegeneration.
Gene–Disease AssociationStrongMultiple studies identified 12 constitutively active variants out of 42 examined in over 8500 ALS patients, demonstrating a robust association (PMID:34991663, PMID:34796871). Genetic EvidenceStrongPatient-specific missense and in‑frame deletion variants, including c.550G>A (p.Val184Gly), disrupt normal autoinhibition and consistently show gain‑of‑function effects in unrelated cases. Functional EvidenceStrongExperimental assays in neuronal cultures and mouse models, along with structural studies revealing an octameric ring essential for enzymatic activity, underline the pathogenic mechanism driven by hyperactive SARM1 variants. |