{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T22:21:04Z","timestamp":1793744464336,"version":"4.6.1"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T00:00:00Z","timestamp":1721001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>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 <jats:italic>KIF1A<\/jats:italic>, responsible for encoding a kinesin-3 motor protein that carries synaptic vesicles, is considered a genetic predisposing factor for ALS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The analysis of whole-exome sequencing data from 1,068 patients was conducted to examine the genetic link between ALS and <jats:italic>KIF1A<\/jats:italic>. For patients with <jats:italic>KIF1A<\/jats:italic> gene mutations and a family history, we extended the analysis to their families and reanalyzed them using Sanger sequencing for cosegregation analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In our cohort, the <jats:italic>KIF1A<\/jats:italic> mutation frequency was 1.31% (14\/1,068). Thirteen nonsynonymous variants were detected in 14 ALS patients. Consistent with the connection between <jats:italic>KIF1A<\/jats:italic> and ALS, the missense mutation p.A1083T (c.3247G&amp;gt;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 <jats:italic>KIF1A<\/jats:italic> which were linked to hereditary peripheral neuropathy and spastic paraplegia. We observed high clinical heterogeneity in ALS patients with missense mutations in the <jats:italic>KIF1A<\/jats:italic> gene. <jats:italic>KIF5A<\/jats:italic> is a more frequent determinant of ALS in the European population, while <jats:italic>KIF1A<\/jats:italic> accounts for a similar proportion of ALS in both the European and Chinese populations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our investigation revealed that mutations in the C-terminus of <jats:italic>KIF1A<\/jats:italic> could increase the risk of ALS, support the pathogenic role of <jats:italic>KIF1A<\/jats:italic> in ALS and expand the phenotypic and genetic spectrum of <jats:italic>KIF1A<\/jats:italic>-related ALS.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnagi.2024.1421841","type":"journal-article","created":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T05:02:26Z","timestamp":1721019746000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Genetic link between KIF1A mutations and amyotrophic lateral sclerosis: evidence from whole-exome sequencing"],"prefix":"10.3389","volume":"16","author":[{"given":"Wei","family":"Zheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyi","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxuan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongsheng","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,7,15]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"e2113795119","DOI":"10.1073\/pnas.2113795119","article-title":"De novo mutations in KIF1A-associated neuronal disorder (KAND) dominant-negatively inhibit motor activity and axonal transport of synaptic vesicle precursors","volume":"119","author":"Anazawa","year":"2022","journal-title":"Proc. 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