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Neuron. 2014 Oct 22;84(2):324-31. doi: 10.1016/j.neuron.2014.09.027. Epub 2014 Oct 22.

Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS.

Author information

1
Centre for Neurodegeneration Research, King's College London, Department of Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, London, SE5 8AF, UK.
2
Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy; Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center - Università degli Studi di Milano, 20122 Milan, Italy.
3
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
4
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Republic of Ireland.
5
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Bioinformatics and Computational Biology, Worcester Polytechnic Institute, Worcester, MA 01609, USA.
6
Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy.
7
Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', 20133 Milan, Italy.
8
Neurogenetics Group, Division of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building, Du Cane Road, London, W12 0NN, UK.
9
Department of Genome analysis and Neurogenetics, Academic Medical Centre, Amsterdam, The Netherlands.
10
Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Republic of Ireland.
11
Department of Neurology, Emory University, Atlanta, GA 30322, USA.
12
Unidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid, SERMAS, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER U-723), 28041 Madrid, Spain.
13
Unidad de ELA, Instituto de Investigación Hospital Gregorio Marañón de Madrid, SERMAS, 28007 Madrid, Spain.
14
Department of Genetics and Molecular Medicine, King's College London, Tower Wing, Guy's Hospital, London, SE1 7EH, UK.
15
Department of Neurology, Brain Center Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, 3508 GA Utrecht, the Netherlands.
16
3rd Neurology Unit, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', 20133 Milan, Italy.
17
Department of Medical Biotechnology and Translational Medicine - Università degli Studi di Milano, 20133 Milan, Italy.
18
Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center - Università degli Studi di Milano, 20122 Milan, Italy; Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
19
Experimental Neurobiology Laboratory, IRCCS 'C. Mondino' National Neurological Institute, 27100 Pavia, Italy.
20
Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), "A. Avogadro" University, 28100 Novara, Italy.
21
Department of Neurosciences, University of Padova, 35122 Padova, Italy.
22
School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK; Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2WB, UK.
23
Australian School of Advanced Medicine, Macquarie University, Sydney, NSW 2109, Australia.
24
Australian School of Advanced Medicine, Macquarie University, Sydney, NSW 2109, Australia; Northcott Neuroscience Laboratory, University of Sydney, ANZAC Research Institute, Sydney, NSW 2139, Australia.
25
Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, 3801 Montreal, QC H3A 2B4, Canada.
26
Department of Clinical Neuroscience, Medical Research Council Centre for Neurodegeneration Research, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, WC2R 2LS, UK.
27
School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
28
Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, S10 2HQ, UK.
29
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK.
30
Department of Bioinformatics and Computational Biology, Worcester Polytechnic Institute, Worcester, MA 01609, USA.
31
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: john.landers@umassmed.edu.

Abstract

Exome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analysis.

PMID:
25374358
PMCID:
PMC4521390
DOI:
10.1016/j.neuron.2014.09.027
[Indexed for MEDLINE]
Free PMC Article

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