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

Bradley N Smith; Karen Morrison; Hardev Pall; Nicola Ticozzi; Claudia Fallini; Athina Soragia Gkazi; Simon Topp; Kevin P Kenna; Emma L Scotter; Jason Kost; Pamela Keagle; Jack W Miller; Daniela Calini; Caroline Vance; Eric W Danielson; Claire Troakes; Cinzia Tiloca; Safa Al-Sarraj; Elizabeth A Lewis; Andrew King; Claudia Colombrita; Viviana Pensato; Barbara Castellotti; Jacqueline de Belleroche; Frank Baas; Anneloor L M A ten Asbroek; Peter C Sapp; Diane McKenna-Yasek; Russell L McLaughlin; Meraida Polak; Seneshaw Asress; Jesús Esteban-Pérez; José Luis Muñoz-Blanco; Michael Simpson; Wouter van Rheenen; Frank P Diekstra; Giuseppe Lauria; Stefano Duga; Stefania Corti; Cristina Cereda; Lucia Corrado; Gianni Sorarù; Kelly L Williams; Garth A Nicholson; Ian P Blair; Patrick A Dion; Claire S Leblond; Guy A Rouleau; Orla Hardiman; Jan H Veldink; SLAGEN Consortium

doi:10.1016/j.neuron.2014.09.027

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

Bradley N Smith, Karen Morrison, Hardev Pall, Nicola Ticozzi, Claudia Fallini, Athina Soragia Gkazi, Simon Topp, Kevin P Kenna, Emma L Scotter, Jason Kost, Pamela Keagle, Jack W Miller, Daniela Calini, Caroline Vance, Eric W Danielson, Claire Troakes, Cinzia Tiloca, Safa Al-Sarraj, Elizabeth A Lewis, Andrew KingClaudia Colombrita, Viviana Pensato, Barbara Castellotti, Jacqueline de Belleroche, Frank Baas, Anneloor L M A ten Asbroek, Peter C Sapp, Diane McKenna-Yasek, Russell L McLaughlin, Meraida Polak, Seneshaw Asress, Jesús Esteban-Pérez, José Luis Muñoz-Blanco, Michael Simpson, Wouter van Rheenen, Frank P Diekstra, Giuseppe Lauria, Stefano Duga, Stefania Corti, Cristina Cereda, Lucia Corrado, Gianni Sorarù, Kelly L Williams, Garth A Nicholson, Ian P Blair, Patrick A Dion, Claire S Leblond, Guy A Rouleau, Orla Hardiman, Jan H Veldink, SLAGEN Consortium

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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.

Original language	English
Pages (from-to)	324-31
Number of pages	8
Journal	Neuron
Volume	84
Issue number	2
DOIs	https://doi.org/10.1016/j.neuron.2014.09.027
Publication status	Published - 22 Oct 2014

Keywords

Amyotrophic Lateral Sclerosis
Brain
Exome
Genetic Predisposition to Disease
Humans
Mutation
Neurons
Sequence Analysis, DNA
Tubulin

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.neuron.2014.09.027

Morrison_Exome-wide_Rare_Variant_Neuron_2014
NOTICE: this is the author’s version of a work that was accepted for publication in Neuron. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Neuron, VOL 84, ISSUE 2, 22 October 2014 DOI:10.1016/j.neuron.2014.09.027 Eligibility for repository checked February 2015
Accepted author manuscript, 3.34 MBLicence: None: All rights reserved

Cite this

Smith, B. N., Morrison, K., Pall, H., Ticozzi, N., Fallini, C., Gkazi, A. S., Topp, S., Kenna, K. P., Scotter, E. L., Kost, J., Keagle, P., Miller, J. W., Calini, D., Vance, C., Danielson, E. W., Troakes, C., Tiloca, C., Al-Sarraj, S., Lewis, E. A., ... SLAGEN Consortium (2014). Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS. Neuron, 84(2), 324-31. https://doi.org/10.1016/j.neuron.2014.09.027

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title = "Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS",

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.",

keywords = "Amyotrophic Lateral Sclerosis, Brain, Exome, Genetic Predisposition to Disease, Humans, Mutation, Neurons, Sequence Analysis, DNA, Tubulin",

author = "Smith, {Bradley N} and Karen Morrison and Hardev Pall and Nicola Ticozzi and Claudia Fallini and Gkazi, {Athina Soragia} and Simon Topp and Kenna, {Kevin P} and Scotter, {Emma L} and Jason Kost and Pamela Keagle and Miller, {Jack W} and Daniela Calini and Caroline Vance and Danielson, {Eric W} and Claire Troakes and Cinzia Tiloca and Safa Al-Sarraj and Lewis, {Elizabeth A} and Andrew King and Claudia Colombrita and Viviana Pensato and Barbara Castellotti and {de Belleroche}, Jacqueline and Frank Baas and {ten Asbroek}, {Anneloor L M A} and Sapp, {Peter C} and Diane McKenna-Yasek and McLaughlin, {Russell L} and Meraida Polak and Seneshaw Asress and Jes{\'u}s Esteban-P{\'e}rez and Mu{\~n}oz-Blanco, {Jos{\'e} Luis} and Michael Simpson and {van Rheenen}, Wouter and Diekstra, {Frank P} and Giuseppe Lauria and Stefano Duga and Stefania Corti and Cristina Cereda and Lucia Corrado and Gianni Sorar{\`u} and Williams, {Kelly L} and Nicholson, {Garth A} and Blair, {Ian P} and Dion, {Patrick A} and Leblond, {Claire S} and Rouleau, {Guy A} and Orla Hardiman and Veldink, {Jan H} and {SLAGEN Consortium}",

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doi = "10.1016/j.neuron.2014.09.027",

language = "English",

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journal = "Neuron",

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Smith, BN, Morrison, K, Pall, H, Ticozzi, N, Fallini, C, Gkazi, AS, Topp, S, Kenna, KP, Scotter, EL, Kost, J, Keagle, P, Miller, JW, Calini, D, Vance, C, Danielson, EW, Troakes, C, Tiloca, C, Al-Sarraj, S, Lewis, EA, King, A, Colombrita, C, Pensato, V, Castellotti, B, de Belleroche, J, Baas, F, ten Asbroek, ALMA, Sapp, PC, McKenna-Yasek, D, McLaughlin, RL, Polak, M, Asress, S, Esteban-Pérez, J, Muñoz-Blanco, JL, Simpson, M, van Rheenen, W, Diekstra, FP, Lauria, G, Duga, S, Corti, S, Cereda, C, Corrado, L, Sorarù, G, Williams, KL, Nicholson, GA, Blair, IP, Dion, PA, Leblond, CS, Rouleau, GA, Hardiman, O, Veldink, JH & SLAGEN Consortium 2014, 'Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS', Neuron, vol. 84, no. 2, pp. 324-31. https://doi.org/10.1016/j.neuron.2014.09.027

TY - JOUR

T1 - Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS

AU - Smith, Bradley N

AU - Morrison, Karen

AU - Pall, Hardev

AU - Ticozzi, Nicola

AU - Fallini, Claudia

AU - Gkazi, Athina Soragia

AU - Topp, Simon

AU - Kenna, Kevin P

AU - Scotter, Emma L

AU - Kost, Jason

AU - Keagle, Pamela

AU - Miller, Jack W

AU - Calini, Daniela

AU - Vance, Caroline

AU - Danielson, Eric W

AU - Troakes, Claire

AU - Tiloca, Cinzia

AU - Al-Sarraj, Safa

AU - Lewis, Elizabeth A

AU - King, Andrew

AU - Colombrita, Claudia

AU - Pensato, Viviana

AU - Castellotti, Barbara

AU - de Belleroche, Jacqueline

AU - Baas, Frank

AU - ten Asbroek, Anneloor L M A

AU - Sapp, Peter C

AU - McKenna-Yasek, Diane

AU - McLaughlin, Russell L

AU - Polak, Meraida

AU - Asress, Seneshaw

AU - Esteban-Pérez, Jesús

AU - Muñoz-Blanco, José Luis

AU - Simpson, Michael

AU - van Rheenen, Wouter

AU - Diekstra, Frank P

AU - Lauria, Giuseppe

AU - Duga, Stefano

AU - Corti, Stefania

AU - Cereda, Cristina

AU - Corrado, Lucia

AU - Sorarù, Gianni

AU - Williams, Kelly L

AU - Nicholson, Garth A

AU - Blair, Ian P

AU - Dion, Patrick A

AU - Leblond, Claire S

AU - Rouleau, Guy A

AU - Hardiman, Orla

AU - Veldink, Jan H

AU - SLAGEN Consortium

PY - 2014/10/22

Y1 - 2014/10/22

N2 - 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.

AB - 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.

KW - Amyotrophic Lateral Sclerosis

KW - Brain

KW - Exome

KW - Genetic Predisposition to Disease

KW - Humans

KW - Mutation

KW - Neurons

KW - Sequence Analysis, DNA

KW - Tubulin

U2 - 10.1016/j.neuron.2014.09.027

DO - 10.1016/j.neuron.2014.09.027

M3 - Article

C2 - 25374358

SN - 0896-6273

VL - 84

SP - 324

EP - 331

JO - Neuron

JF - Neuron

IS - 2

ER -

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

Abstract

Keywords

UN SDGs

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