Journal
NEURON
Volume 97, Issue 6, Pages 1268-+Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2018.02.027
Keywords
-
Categories
Funding
- ALS Association (ALSA) [15-LGCA-235, 15-LGCA-234, 17-LGCA-331, 16-LGCA-310, 16-LGCA-308]
- NeuroLINCS, an NIH
- ALS liga Belgie
- Flanders Innovation & Enterpreneurship (IWT grant Project MinE)
- Belgian National Lottery
- Opening the Future Fund (KU Leuven)
- E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders
- ERC [340429]
- NINDS [R35 NS097261, P01NS084974]
- Suna and Inan Kirac Foundation, Istanbul, TR
- Heaton-Ellis Trust
- Middlemass Family
- Motor Neurone Disease Association
- Medical Research Council
- Medical Research Foundation
- Psychiatry Research Trust of the Institute of Psychiatry
- Guy's and St Thomas' Charity
- Wellcome Trust
- Noreen Murray Foundation
- UK Dementia Research Institute - Medical Research Council
- Alzheimer's Society
- Alzheimer's Research UK
- Medical Research Foundation (MRF) [MRF-060-0003-RG-SMITH]
- Massachusetts Institute of Technology, Howard Hughes Institute
- Department of Veterans Affairs [P30AG13846]
- NIH [P30AG13846]
- Motor Neurone Disease Research Institute of Australia [1107644, 1095215]
- National Health and Medical Research Council of Australia [1107644, 1095215]
- MRC/MNDA LEWF
- NIHR UCLH BRC
- NIH/NIEHS [K23ES027221]
- ALS Association
- Target ALS [90072272]
- Cytokinetics
- ALS Finding a Cure
- AriSLA - Fondazione Italiana di Ricerca per la SLA (grant EXOMEFALS)
- AriSLA - Fondazione Italiana di Ricerca per la SLA (grant NOVALS)
- Italian Ministry of Health [GR-2011-02347820 - IRisALS, ICS110.1/RF97.71]
- Science Foundation Ireland
- MND Association of England
- MND Association of Wales
- MND Association of Northern Ireland
- Health Research Board Clinician Scientist Programme
- NIHR [NF-SI-0512-10082]
- Sheffield NIHR Biomedical Research Centre for Translational Neuroscience [IS-BRC-1215-20017]
- Italian Ministry of Health (Ricerca Finalizzata)
- Regione Piemonte (Ricerca Finalizzata)
- University of Turin
- Fondazione Vialli e Mauro onlus
- European Commission (Health Seventh Framework Programme)
- Swedish Brain Foundation
- Swedish Science Council
- Knut and Alice Wallenberg Foundation
- Bertil Hallsten Foundation
- Ulla-Carin Lindquist Foundation
- Neuroforbundet Association
- Torsten and Ragnar Soderberg Foundation
- Stratneuro Initiative
- Vasterbotten County Council
- Angel Fund
- Project ALS/P2ALS
- ALS Therapy Alliance
- Canadian Consortium on Neurodegeneration in Aging
- Helsinki University Hospital [294817]
- Academy of Finland [294817]
- Sigrid Juselius Foundation
- Muscular Dystrophy Association
- NIH/NINDS [R01NS073873]
- MND Association
- NeuroLINCS [NIH U54 NS091046]
- TOW Foundation
- NCATS
- NINDS
- United States National Institute on Aging [263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111, N01-AG5-0002]
- Intramural Research Programs of the NIH, National Institute on Aging [Z01-AG000949-02]
- National Institute of Neurological Disorders and Stroke
- Merck Co., Inc.
- Center for Disease Control and Prevention
- Microsoft Research
- Packard Center for ALS Research at Johns Hopkins
- UK MND Association
- Medical Research Council (MRC) UK
- Wellcome Trust/MRC Joint Call in Neurodegeneration Award
- MRC Neuromuscular Centre
- UK National Institute for Health Research Biomedical Research Unit
- Italian Health Ministry (Ricerca Sanitaria Finalizzata)
- Compagnia di San Paolo
- European Community [259867]
- New York Brain Bank-The Taub Institute, Columbia University, Department of Veterans Affairs Biorepository Brain Bank [BX002466]
- [NINDS/NS061867]
- National Health and Medical Research Council of Australia [1107644] Funding Source: NHMRC
- European Research Council (ERC) [340429] Funding Source: European Research Council (ERC)
- Academy of Medical Sciences (AMS) [SGL018\\1007] Funding Source: researchfish
- Medical Research Council [G0600974, MR/R024804/1, G0500289, MR/M008606/1, G0900688, UKDRI-6001, MR/L016397/1, MC_PC_17115, MR/L501529/1, MR/L021803/1] Funding Source: researchfish
- Medical Research Foundation [MRF-060-0003-RG-SMITH] Funding Source: researchfish
- Motor Neurone Disease Association [Malaspina/Apr13/817-791, Smith/Oct16/888-792, AlChalabi-Dobson/Apr14/829-791, Shaw/Nov14/985-797, Smith/Apr16/847-791, Fratta/Jan15/946-795, Shaw/Apr15/933-794, McLaughlin/Oct15/957-799] Funding Source: researchfish
- National Institute for Health Research [CL-2015-04-001, NF-SI-0512-10082, NF-SI-0617-10077] Funding Source: researchfish
- Rosetrees Trust [M599] Funding Source: researchfish
- MRC [MR/L021803/1, G0600974, G0500289, MR/M008606/1, G0900688, MR/R024804/1, MC_PC_17115, MR/K01014X/1, MR/L016397/1, UKDRI-6001] Funding Source: UKRI
Ask authors/readers for more resources
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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