Genetic Link Between Mutations and Amyotrophic Lateral Sclerosis: Evidence from Whole-exome Sequencing

Objectives: Genetics have been shown to have a substantial impact on amyotrophic lateral sclerosis (ALS). The ALS process involves defects in axonal transport and cytoskeletal dynamics. It has been identified that , responsible for encoding a kinesin-3 motor protein that carries synaptic vesicles, is considered a genetic predisposing factor for ALS.

Methods: The analysis of whole-exome sequencing data from 1,068 patients was conducted to examine the genetic link between ALS and . For patients with gene mutations and a family history, we extended the analysis to their families and reanalyzed them using Sanger sequencing for cosegregation analysis.

Results: In our cohort, the mutation frequency was 1.31% (14/1,068). Thirteen nonsynonymous variants were detected in 14 ALS patients. Consistent with the connection between and ALS, the missense mutation p.A1083T (c.3247G>A) was shown to cosegregate with disease. The mutations related to ALS in our study were primarily located in the cargo-binding region at the C-terminal, as opposed to the mutations of motor domain at the N-terminal of which were linked to hereditary peripheral neuropathy and spastic paraplegia. We observed high clinical heterogeneity in ALS patients with missense mutations in the gene. is a more frequent determinant of ALS in the European population, while accounts for a similar proportion of ALS in both the European and Chinese populations.

Conclusion: Our investigation revealed that mutations in the C-terminus of could increase the risk of ALS, support the pathogenic role of in ALS and expand the phenotypic and genetic spectrum of -related ALS.