Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS.
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.
Centre for Neurodegeneration Research, King's College London, Department of Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, London, SE5 8AF, UK.
Bradley N
BN
Smith
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.
Nicola
N
Ticozzi
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Claudia
C
Fallini
Centre for Neurodegeneration Research, King's College London, Department of Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, London, SE5 8AF, UK.
Athina Soragia
AS
Gkazi
Centre for Neurodegeneration Research, King's College London, Department of Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, London, SE5 8AF, UK.
Simon
S
Topp
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.
Kevin P
KP
Kenna
Centre for Neurodegeneration Research, King's College London, Department of Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, London, SE5 8AF, UK.
Emma L
EL
Scotter
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.
Jason
J
Kost
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Pamela
P
Keagle
Centre for Neurodegeneration Research, King's College London, Department of Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, London, SE5 8AF, UK.
Jack W
JW
Miller
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.
Daniela
D
Calini
Centre for Neurodegeneration Research, King's College London, Department of Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, London, SE5 8AF, UK.
Caroline
C
Vance
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Eric W
EW
Danielson
Centre for Neurodegeneration Research, King's College London, Department of Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, London, SE5 8AF, UK.
Claire
C
Troakes
Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy.
Cinzia
C
Tiloca
Centre for Neurodegeneration Research, King's College London, Department of Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, London, SE5 8AF, UK.
Safa
S
Al-Sarraj
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Elizabeth A
EA
Lewis
Centre for Neurodegeneration Research, King's College London, Department of Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, London, SE5 8AF, UK.
Andrew
A
King
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.
Claudia
C
Colombrita
Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', 20133 Milan, Italy.
Viviana
V
Pensato
Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', 20133 Milan, Italy.
Barbara
B
Castellotti
Neurogenetics Group, Division of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building, Du Cane Road, London, W12 0NN, UK.
Jacqueline
J
de Belleroche
Department of Genome analysis and Neurogenetics, Academic Medical Centre, Amsterdam, The Netherlands.
Frank
F
Baas
Department of Genome analysis and Neurogenetics, Academic Medical Centre, Amsterdam, The Netherlands.
Anneloor L M A
AL
ten Asbroek
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Peter C
PC
Sapp
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Diane
D
McKenna-Yasek
Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Republic of Ireland.
Russell L
RL
McLaughlin
Department of Neurology, Emory University, Atlanta, GA 30322, USA.
Meraida
M
Polak
Department of Neurology, Emory University, Atlanta, GA 30322, USA.
Seneshaw
S
Asress
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.
Jesús
J
Esteban-Pérez
Unidad de ELA, Instituto de Investigación Hospital Gregorio Marañón de Madrid, SERMAS, 28007 Madrid, Spain.
José Luis
JL
Muñoz-Blanco
Department of Genetics and Molecular Medicine, King's College London, Tower Wing, Guy's Hospital, London, SE1 7EH, UK.
Michael
M
Simpson
Department of Neurology, Brain Center Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, 3508 GA Utrecht, the Netherlands.
Wouter
W
van Rheenen
Department of Neurology, Brain Center Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, 3508 GA Utrecht, the Netherlands.
Frank P
FP
Diekstra
3rd Neurology Unit, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', 20133 Milan, Italy.
Giuseppe
G
Lauria
Department of Medical Biotechnology and Translational Medicine - Università degli Studi di Milano, 20133 Milan, Italy.
Stefano
S
Duga
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.
Stefania
S
Corti
Experimental Neurobiology Laboratory, IRCCS 'C. Mondino' National Neurological Institute, 27100 Pavia, Italy.
Cristina
C
Cereda
Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), "A. Avogadro" University, 28100 Novara, Italy.
Lucia
L
Corrado
Department of Neurosciences, University of Padova, 35122 Padova, Italy.
Gianni
G
Sorarù
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.
Karen E
KE
Morrison
Australian School of Advanced Medicine, Macquarie University, Sydney, NSW 2109, Australia.
Kelly L
KL
Williams
Australian School of Advanced Medicine, Macquarie University, Sydney, NSW 2109, Australia; Northcott Neuroscience Laboratory, University of Sydney, ANZAC Research Institute, Sydney, NSW 2139, Australia.
Garth A
GA
Nicholson
Australian School of Advanced Medicine, Macquarie University, Sydney, NSW 2109, Australia.
Ian P
IP
Blair
Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, 3801 Montreal, QC H3A 2B4, Canada.
Patrick A
PA
Dion
Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, 3801 Montreal, QC H3A 2B4, Canada.
Claire S
CS
Leblond
Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, 3801 Montreal, QC H3A 2B4, Canada.
Guy A
GA
Rouleau
Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Republic of Ireland.
Orla
O
Hardiman
Department of Neurology, Brain Center Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, 3508 GA Utrecht, the Netherlands.
Jan H
JH
Veldink
Department of Neurology, Brain Center Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, 3508 GA Utrecht, the Netherlands.
Leonard H
LH
van den Berg
Department of Clinical Neuroscience, Medical Research Council Centre for Neurodegeneration Research, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, WC2R 2LS, UK.
Ammar
A
Al-Chalabi
School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
Hardev
H
Pall
Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, S10 2HQ, UK.
Pamela J
PJ
Shaw
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK.
Martin R
MR
Turner
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK.
Kevin
K
Talbot
Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', 20133 Milan, Italy.
Franco
F
Taroni
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.
Alberto
A
García-Redondo
Department of Bioinformatics and Computational Biology, Worcester Polytechnic Institute, Worcester, MA 01609, USA.
Zheyang
Z
Wu
Department of Neurology, Emory University, Atlanta, GA 30322, USA.
Jonathan D
JD
Glass
Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', 20133 Milan, Italy.
Cinzia
C
Gellera
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.
Antonia
A
Ratti
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Robert H
RH
Brown
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.
Vincenzo
V
Silani
Centre for Neurodegeneration Research, King's College London, Department of Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, London, SE5 8AF, UK.
Christopher E
CE
Shaw
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: john.landers@umassmed.edu.
John E
JE
Landers
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D059472:Exome / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014404:Tubulin / Q000235:genetics* / Q000378:metabolism
C533522:TUBA1A protein, human; D014404:Tubulin