TY - JOUR
T1 - Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS
AU - AUTHOR GROUP
AU - Smith, Bradley N.
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 - Morrison, Karen E.
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 - van den Berg, Leonard H.
PY - 2014
Y1 - 2014
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
U2 - https://doi.org/10.1016/j.neuron.2014.09.027
DO - https://doi.org/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 -