Genome wide analyses identify KIF5A as a novel ALS Gene
File(s)
Accepted version
Author(s)
Nicolas, Aude
de Belleroche, JS
Type
Journal Article
Abstract
To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a
genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we
performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls.
Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated
with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are
causative for two neurodegenerative diseases, hereditary spastic paraplegia (SPG10) and Charcot-MarieTooth
Type 2 (CMT2). In contrast, ALS associated mutations are primarily located at the C-terminal
cargo-binding tail domain and patients harboring loss of function mutations displayed an extended
survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum
resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of
ALS
genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we
performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls.
Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated
with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are
causative for two neurodegenerative diseases, hereditary spastic paraplegia (SPG10) and Charcot-MarieTooth
Type 2 (CMT2). In contrast, ALS associated mutations are primarily located at the C-terminal
cargo-binding tail domain and patients harboring loss of function mutations displayed an extended
survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum
resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of
ALS
Date Issued
2018-03-21
Date Acceptance
2018-02-07
Citation
Neuron, 2018, 97 (6), pp.1268-1283.e
ISSN
0896-6273
Publisher
Elsevier
Start Page
1268
End Page
1283.e
Journal / Book Title
Neuron
Volume
97
Issue
6
Copyright Statement
© 2018 Elsevier Inc. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor
Medical Research Council (MRC)
Grant Number
G0900688
Subjects
1109 Neurosciences
1702 Cognitive Science
Neurology & Neurosurgery
Publication Status
Published
Date Publish Online
2018-03-21