ITALSGEN Consortium , Genomic Translation ALS Care GTAC , ALS Sequencing Consortium , NYGC ALS Consortium , Answer ALS Fdn , Clinical Res ALS Related Disorders , SLAGEN Consortium , French ALS Consortium & Project MinE ALS Sequencing Consor 2018 , ' Genome-wide Analyses Identify KIF5A as a Novel ALS Gene ' , Neuron , vol. 97 , no. 6 , pp. 1268-+ . https://doi.org/10.1016/j.neuron.2018.02.027
Title: | Genome-wide Analyses Identify KIF5A as a Novel ALS Gene |
Author: | ITALSGEN Consortium; Genomic Translation ALS Care GTAC; ALS Sequencing Consortium; NYGC ALS Consortium; Answer ALS Fdn; Clinical Res ALS Related Disorders; SLAGEN Consortium; French ALS Consortium; Project MinE ALS Sequencing Consor |
Contributor organization: | Department of Neurosciences Pentti Tienari / Principal Investigator Neurologian yksikkö Research Programs Unit Clinicum Research Programme for Molecular Neurology University of Helsinki Medicum Department of Pathology HUS Neurocenter |
Date: | 2018-03-21 |
Language: | eng |
Number of pages: | 21 |
Belongs to series: | Neuron |
ISSN: | 0896-6273 |
DOI: | https://doi.org/10.1016/j.neuron.2018.02.027 |
URI: | http://hdl.handle.net/10138/301252 |
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-Marie-Tooth 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. |
Subject: |
AMYOTROPHIC-LATERAL-SCLEROSIS
KINESIN HEAVY-CHAIN DNA-DAMAGE AXONAL-TRANSPORT HEXANUCLEOTIDE REPEAT TARGETED DISRUPTION GENOTYPE IMPUTATION MOTOR-NEURONS FAMILIAL ALS MUTATIONS 3112 Neurosciences 3124 Neurology and psychiatry 3111 Biomedicine |
Peer reviewed: | Yes |
Usage restriction: | openAccess |
Self-archived version: | publishedVersion |
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