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

Smith, Bn; 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, Al; Sapp, Pc; McKenna Yasek, D; McLaughlin, Rl; Polak, M; Asress, S; Esteban Pérez, J; Muñoz Blanco, Jl; Simpson, M; Slagen, Consortium; van Rheenen, W; Diekstra, Fp; Lauria, G; Duga, S; Corti, S; Cereda, C; Corrado, L; Sorarù, G; Morrison, Ke; Williams, Kl; Nicholson, Ga; Blair, Ip; Dion, Pa; Leblond, Cs; Rouleau, Ga; Hardiman, O; Veldink, Jh; van den Berg, Lh; Al Chalabi, A; Pall, H; Shaw, Pj; Turner, Mr; Talbot, K; Taroni, F; García Redondo, A; Wu, Z; Glass, Jd; Ceroni, Mauro; Gellera, C; Ratti, A; Brown, RH Jr; Silani, V; Shaw, Ce; Landers, Je

doi:10.1016/j.neuron.2014.09.027

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.

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Titolo:	Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS
Autori:	Smith, BN 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, AL Sapp, PC McKenna Yasek, D McLaughlin, RL Polak, M Asress, S Esteban Pérez, J Muñoz Blanco, JL Simpson, M SLAGEN Consortium van Rheenen, W Diekstra, FP Lauria, G Duga, S Corti, S Cereda, C Corrado, L Sorarù, G Morrison, KE Williams, KL Nicholson, GA Blair, IP Dion, PA Leblond, CS Rouleau, GA Hardiman, O Veldink, JH van den Berg, LH Al Chalabi, A Pall, H Shaw, PJ Turner, MR Talbot, K Taroni, F García Redondo, A Wu, Z Glass, JD CERONI, MAURO Gellera, C Ratti, A Brown, RH Jr Silani, V Shaw, CE Landers, JE mostra contributor esterni nascondi contributor esterni
Data di pubblicazione:	2014
Rivista:	NEURON
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.
Handle:	http://hdl.handle.net/11571/985458
Appare nelle tipologie:	1.1 Articolo in rivista

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