Genetic link between KIF1A mutations and amyotrophic lateral sclerosis: evidence from whole-exome sequencing

Front Aging Neurosci. 2024 Jul 15:16:1421841. doi: 10.3389/fnagi.2024.1421841. eCollection 2024.

Abstract

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 KIF1A, 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 KIF1A. For patients with KIF1A 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 KIF1A mutation frequency was 1.31% (14/1,068). Thirteen nonsynonymous variants were detected in 14 ALS patients. Consistent with the connection between KIF1A 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 KIF1A which were linked to hereditary peripheral neuropathy and spastic paraplegia. We observed high clinical heterogeneity in ALS patients with missense mutations in the KIF1A gene. KIF5A is a more frequent determinant of ALS in the European population, while KIF1A 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 KIF1A could increase the risk of ALS, support the pathogenic role of KIF1A in ALS and expand the phenotypic and genetic spectrum of KIF1A-related ALS.

Keywords: KIF1A; KIF5A; amyotrophic lateral sclerosis; axonal transport; cosegregation analysis.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. WZ was funded by Beijing Natural Science Foundation (7244428), Peking University Medicine Sailing Program for Young Scholars’ Scientific and Technological Innovation (BMU2023YFJHPY034). DF was funded by the National Natural Science Foundation of China (81873784 and 82071426), Clinical Cohort Construction Program of Peking University Third Hospital (BYSYDL2019002). XL was supported by Beijing Natural Science Foundation (7242170), Clinical Cohort Construction Program of Peking University Third Hospital (BYSYDL2021007, BYSYZD2022009).