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 L M A ten Asbroek; Peter C. Sapp; Diane McKenna-Yasek; Russell L. McLaughlin; Meraida Polak; Seneshaw Asress; Jesús Esteban-Pérez; JoséLuis L. 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; 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, 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 PensatoBarbara 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, JoséLuis L. 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^*, SLAGEN Consortium

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

287 Citations (Scopus)

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 exomewide 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)	324-331
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 - 28 Oct 2014

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Smith, B. N., 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., King, A., Colombrita, C., ... SLAGEN Consortium (2014). Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS. Neuron, 84(2), 324-331. https://doi.org/10.1016/j.neuron.2014.09.027

@article{3a0f34c6b9b34b8e8b20e535956a299f,

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 exomewide 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.",

author = "Smith, {Bradley N.} 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 L.} 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 Morrison, {Karen E.} 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 {Van Den Berg}, {Leonard H.} and Ammar Al-Chalabi and Hardev Pall and Shaw, {Pamela J.} and Turner, {Martin R.} and Kevin Talbot and Franco Taroni and Alberto Garc{\'i}a-Redondo and Zheyang Wu and Glass, {Jonathan D.} and Cinzia Gellera and Antonia Ratti and Brown, {Robert H.} and Vincenzo Silani and Shaw, {Christopher E.} and Landers, {John E.} and {SLAGEN Consortium}",

year = "2014",

month = oct,

day = "28",

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

language = "English",

volume = "84",

pages = "324--331",

journal = "Neuron",

issn = "0896-6273",

publisher = "Cell Press",

number = "2",

}

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, 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, 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, Gellera, C, Ratti, A, Brown, RH, Silani, V, Shaw, CE, Landers, JE & SLAGEN Consortium 2014, 'Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS', Neuron, vol. 84, no. 2, pp. 324-331. 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 - 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, JoséLuis L.

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.

AU - Al-Chalabi, Ammar

AU - Pall, Hardev

AU - Shaw, Pamela J.

AU - Turner, Martin R.

AU - Talbot, Kevin

AU - Taroni, Franco

AU - García-Redondo, Alberto

AU - Wu, Zheyang

AU - Glass, Jonathan D.

AU - Gellera, Cinzia

AU - Ratti, Antonia

AU - Brown, Robert H.

AU - Silani, Vincenzo

AU - Shaw, Christopher E.

AU - Landers, John E.

AU - SLAGEN Consortium

PY - 2014/10/28

Y1 - 2014/10/28

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 exomewide 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 exomewide 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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U2 - 10.1016/j.neuron.2014.09.027

DO - 10.1016/j.neuron.2014.09.027

M3 - Article

C2 - 25374358

AN - SCOPUS:84908224269

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

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