Exome-wide Rare Variant Analysis Identifies TUBA4A Mutations Associated with Familial ALS

被引：296

作者：

Smith, Bradley N. ^{[1
]}

Ticozzi, Nicola ^{[2
,3
]}

Fallini, Claudia ^{[4
]}

Gkazi, Athina Soragia ^{[1
]}

Topp, Simon ^{[1
]}

Kenna, Kevin P. ^{[4
,5
]}

Scotter, Emma L. ^{[1
]}

Kost, Jason ^{[4
]}

Keagle, Pamela ^{[4
]}

Miller, Jack W. ^{[1
]}

Calini, Daniela ^{[2
,3
]}

Vance, Caroline ^{[1
]}

Danielson, Eric W. ^{[4
]}

Troakes, Claire ^{[1
]}

Tiloca, Cinzia ^{[2
]}

Al-Sarraj, Safa ^{[1
]}

Lewis, Elizabeth A. ^{[4
]}

King, Andrew ^{[1
]}

Colombrita, Claudia ^{[2
,3
]}

Pensato, Viviana ^{[6
]}

Castellotti, Barbara ^{[6
]}

De Belleroche, Jacqueline ^{[7
]}

Baas, Frank ^{[8
]}

ten Asbroek, Anneloor L. M. A. ^{[8
]}

Sapp, Peter C. ^{[4
]}

McKenna-Yasek, Diane ^{[4
]}

McLaughlin, Russell L. ^{[5
]}

Polak, Meraida ^{[9
]}

Asress, Seneshaw ^{[9
]}

Esteban-Perez, Jesus ^{[10
,11
]}

Munoz-Blanco, Jose Luis ^{[12
]}

Simpson, Michael ^{[13
]}

van Rheenen, Wouter ^{[14
]}

Diekstra, Frank P. ^{[14
]}

Lauria, Giuseppe ^{[15
]}

Duga, Stefano ^{[16
]}

Corti, Stefania ^{[3
,17
]}

Cereda, Cristina ^{[18
]}

Corrado, Lucia ^{[19
]}

Soraru, Gianni ^{[20
]}

Morrison, Karen E. ^{[21
,22
]}

Williams, Kelly L. ^{[23
]}

Nicholson, Garth A. ^{[23
,24
]}

Blair, Ian P. ^{[23
]}

Dion, Patrick A. ^{[25
]}

Leblond, Claire S. ^{[25
]}

Rouleau, Guy A. ^{[25
]}

Hardiman, Orla ^{[5
]}

Veldink, Jan H. ^{[14
]}

van den Berg, Leonard H. ^{[14
]}

机构：

[1] Kings Coll London, Ctr Neurodegenerat Res, Dept Clin Neurosci, Inst Psychiat Psychol & Neurosci, London SE5 8AF, England

[2] IRCCS Ist Auxol Italiano, Dept Neurol & Lab Neurosci, I-20149 Milan, Italy

[3] Univ Milan, Dino Ferrari Ctr, Dept Pathophysiol & Transplantat, I-20122 Milan, Italy

[4] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01605 USA

[5] Univ Dublin Trinity Coll, Trinity Biomed Sci Inst, Acad Unit Neurol, Dublin 2, Ireland

[6] Fdn IRCCS Ist Neurol Carlo Besta, Unit Genet Neurodegenerat & Metab Dis, I-20133 Milan, Italy

[7] Univ London Imperial Coll Sci Technol & Med, Neurogenet Grp, Div Brain Sci, London W12 0NN, England

[8] Univ Amsterdam, Acad Med Ctr, Dept Genome Anal & Neurogenet, NL-1105 AZ Amsterdam, Netherlands

[9] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA

[10] Hosp 12 Octubre, SERMAS, Unidad ELA, Inst Invest, E-28041 Madrid, Spain

[11] CIBERER, U 723, Madrid 28041, Spain

[12] Hosp Gen Gregorio Maranon, Inst Invest, Unidad ELA, SERMAS, Madrid 28007, Spain

[13] Guys Hosp, Kings Coll London, Dept Genet & Mol Med, London SE1 7EH, England

[14] Univ Med Ctr Utrecht, Brain Ctr, Dept Neurol, Rudolf Magnus Inst Neurosci, NL-3508 GA Utrecht, Netherlands

[15] Fdn IRCCS Ist Neurol Carlo Besta, Neurol Unit 3, I-20133 Milan, Italy

[16] Univ Milan, Dept Med Biotechnol & Translat Med, I-20133 Milan, Italy

[17] IRCCS Fdn Ca Granda Osped Maggiore Policlin, Neurol Unit, I-20122 Milan, Italy

[18] IRCCS C Mondino Natl Neurol Inst, Expt Neurobiol Lab, I-27100 Pavia, Italy

[19] A Avogadro Univ, IRCAD, Dept Hlth Sci, I-28100 Novara, Italy

[20] Univ Padua, Dept Neurosci, I-35122 Padua, Italy

[21] Univ Birmingham, Coll Med & Dent Sci, Sch Clin & Expt Med, Birmingham B15 2TT, W Midlands, England

[22] Univ Hosp Birmingham NHS Fdn Trust, Queen Elizabeth Hosp, Birmingham B15 2WB, W Midlands, England

[23] Macquarie Univ, Australian Sch Adv Med, Sydney, NSW 2109, Australia

[24] Univ Sydney, ANZAC Res Inst, Northcott Neurosci Lab, Sydney, NSW 2139, Australia

[25] McGill Univ, Dept Neurol & Neurosurg, Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada

[26] Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Clin Neurosci, Med Res Council,Ctr Neurodegenerat Res, London WC2R 2LS, England

[27] Univ Sheffield, Sheffield Inst Translat Neurosci, Sheffield S10 2HQ, S Yorkshire, England

[28] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford OX3 9DU, England

来源：

NEURON | 2014年 / 84卷 / 02期

基金：

美国国家科学基金会; 英国惠康基金; 英国医学研究理事会;

关键词：

AMYOTROPHIC-LATERAL-SCLEROSIS; PROGRESSIVE-MOTOR-NEURONOPATHY; NEURONAL MIGRATION; ALPHA-TUBULIN; CORTICAL DEVELOPMENT; MISSENSE MUTATION; COMPLEX TRAITS; GENE; DISEASE; MICROTUBULES;

D O I：

10.1016/j.neuron.2014.09.027

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

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.

引用

页码：324 / 331

页数：8

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