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Exome-wide Rare Variant Analysis Identifies TUBA4A Mutations Associated with Familial ALS
Bradley N. Smith ,
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 LMA 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 ,
Karen E. Morrison ,
Kelly L. Williams ,
Garth A. Nicholson ,
Ian P. Blair ,
Patrick A. Dion ,
Claire S. Leblond ,
Guy A. Rouleau ,
Orla Hardiman ,
Jan H. Veldink ,
Leonard H. van den Berg ,
Ammar Al-Chalabi ,
Hardev Pall ,
Pamela J. Shaw ,
Martin R. Turner ,
Kevin Talbot ,
Franco Taroni ,
Alberto García-Redondo ,
Zheyang Wu ,
Jonathan D. Glass ,
Cinzia Gellera ,
Antonia Ratti ,
Robert H. Brown ,
Vincenzo Silani ,
Christopher E. Shaw ,
John E. Landers ,
Sandra D’Alfonso ,
Letizia Mazzini ,
Giacomo P. Comi ,
Roberto Del Bo ,
Mauro Ceroni ,
Stella Gagliardi ,
Giorgia Querin ,
Cinzia Bertolin
October 2014
October 2014
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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.