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.

Original languageEnglish
Pages (from-to)1268-1283.e6
JournalNeuron
Volume97
Issue number6
DOIs
Publication statusPublished - Mar 21 2018

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Kinesin
Genome
Mutation
Genes
Hereditary Spastic Paraplegia
Genome-Wide Association Study
Neurodegenerative Diseases
Tooth
Phenotype
Survival

Cite this

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. / ITALSGEN consortium.

In: Neuron, Vol. 97, No. 6, 21.03.2018, p. 1268-1283.e6.

Research output: Contribution to journalArticle

ITALSGEN consortium. / Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. In: Neuron. 2018 ; Vol. 97, No. 6. pp. 1268-1283.e6.
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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.",
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T1 - Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

AU - ITALSGEN consortium

AU - Nicolas, Aude

AU - Kenna, Kevin P

AU - Renton, Alan E

AU - Ticozzi, Nicola

AU - Faghri, Faraz

AU - Chia, Ruth

AU - Dominov, Janice A

AU - Kenna, Brendan J

AU - Nalls, Mike A

AU - Keagle, Pamela

AU - Rivera, Alberto M

AU - van Rheenen, Wouter

AU - Murphy, Natalie A

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AU - Van der Spek, Rick A

AU - Pliner, Hannah A

AU - Shankaracharya, null

AU - Smith, Bradley N

AU - Marangi, Giuseppe

AU - Topp, Simon D

AU - Abramzon, Yevgeniya

AU - Gkazi, Athina Soragia

AU - Eicher, John D

AU - Kenna, Aoife

AU - Mora, Gabriele

AU - Calvo, Andrea

AU - Mazzini, Letizia

AU - Riva, Nilo

AU - Mandrioli, Jessica

AU - Caponnetto, Claudia

AU - Battistini, Stefania

AU - Volanti, Paolo

AU - La Bella, Vincenzo

AU - Conforti, Francesca L

AU - Borghero, Giuseppe

AU - Messina, Sonia

AU - Simone, Isabella L

AU - Trojsi, Francesca

AU - Salvi, Fabrizio

AU - Logullo, Francesco O

AU - D'Alfonso, Sandra

AU - Lauria, Giuseppe

AU - Tiloca, Cinzia

AU - Comi, Giacomo P

AU - Cereda, Cristina

AU - Taroni, Franco

AU - Ratti, Antonia

AU - Gellera, Cinzia

AU - Silani, Vincenzo

N1 - Copyright © 2018 Elsevier Inc. All rights reserved.

PY - 2018/3/21

Y1 - 2018/3/21

N2 - 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.

AB - 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.

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DO - 10.1016/j.neuron.2018.02.027

M3 - Article

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VL - 97

SP - 1268-1283.e6

JO - Neuron

JF - Neuron

SN - 0896-6273

IS - 6

ER -