Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
Item Type:Journal Article
Citation:Nicolas, A. and Kenna, K.P. and Renton, A.E. and Ticozzi, N. and Faghri, F. and Chia, R. and Dominov, J.A. and Kenna, B.J. and Nalls, M.A. and Keagle, P. and Rivera, A.M. and van Rheenen, W. and Murphy, N.A. and van Vugt, J.J.F.A. and Geiger, J.T. and Van der Spek, R.A. and Pliner, H.A. and Shankaracharya and Smith, B.N. and Marangi, G. and Topp, S.D. and Abramzon, Y. and Gkazi, A.S. and Eicher, J.D. and Kenna, A. and Logullo, F.O. and Simone, I.L. and Logroscino, G. and Salvi, F. and Bartolomei, I. and Borghero, G. and Murru, M.R. and Costantino, E. and Pani, C. and Puddu, R. and Caredda, C. and Piras, V. and Tranquilli, S. and Cuccu, S. and Corongiu, D. and Melis, M. and Milia, A. and Marrosu, F. and Marrosu, M.G. and Floris, G. and Cannas, A. and Capasso, M. and Caponnetto, C. and Mancardi, G. and Origone, P. and Mandich, P. and Conforti, F.L. and Cavallaro, S. and Mora, G. and Marinou, K. and Sideri, R. and Penco, S. and Mosca, L. and Lunetta, C. and Pinter, G.L. and Corbo, M. and Riva, N. and Carrera, P. and Volanti, P. and Mandrioli, J. and Fini, N. and Fasano, A. and Tremolizzo, L. and Arosio, A. and Ferrarese, C. and Trojsi, F. and Tedeschi, G. and Monsurr??, M.R. and Piccirillo, G. and Femiano, C. and Ticca, A. and Ortu, E. and La Bella, V. and Spataro, R. and Colletti, T. and Sabatelli, M. and Zollino, M. and Conte, A. and Luigetti, M. and Lattante, S. and Santarelli, M. and Petrucci, A. and Pugliatti, M. and Pirisi, A. and Parish, L.D. and Occhineri, P. and Giannini, F. and Battistini, S. and Ricci, C. and Benigni, M. and Cau, T.B. and Loi, D. and Calvo, A. and Moglia, C. and Brunetti, M. and Barberis, M. and Restagno, G. and Casale, F. and Marrali, G. and Fuda, G. and Ossola, I. and Cammarosano, S. and Canosa, A. and Ilardi, A. and Manera, U. and Grassano, M. and Tanel, R. and Pisano, F. and Mazzini, L. and Messina, S. and D'Alfonso, S. and Corrado, L. and Ferrucci, L. and Harms, M.B. and Goldstein, D.B. and Shneider, N.A. and Goutman, S.A. and Simmons, Z. and Miller, T.M. and Chandran, S. and Pal, S. and Manousakis, G. and Appel, S.H. and Simpson, E. and Wang, L. and Baloh, R.H. and Gibson, S.B. and Bedlack, R. and Lacomis, D. and Sareen, D. and Sherman, A. and Bruijn, L. and Penny, M. and Moreno, C.D.A.M. and Kamalakaran, S. and Allen, A.S. and Boone, B.E. and Brown, R.H. and Carulli, J.P. and Chesi, A. and Chung, W.K. and Cirulli, E.T. and Cooper, G.M. and Couthouis, J. and Day-Williams, A.G. and Dion, P.A. and Gitler, A.D. and Glass, J.D. and Han, Y. and Harris, T. and Hayes, S.D. and Jones, A.L. and Keebler, J. and Krueger, B.J. and Lasseigne, B.N. and Levy, S.E. and Lu, Y.-F. and Maniatis, T. and McKenna-Yasek, D. and Myers, R.M. and Petrovski, S. and Pulst, S.M. and Raphael, A.R. and Ravits, J.M. and Ren, Z. and Rouleau, G.A. and Sapp, P.C. and Sims, K.B. and Staropoli, J.F. and Waite, L.L. and Wang, Q. and Wimbish, J.R. and Xin, W.W. and Phatnani, H. and Kwan, J. and Broach, J. and Arcila-Londono, X. and Lee, E.B. and Van Deerlin, V.M. and Fraenkel, E. and Ostrow, L.W. and Baas, F. and Zaitlen, N. and Berry, J.D. and Malaspina, A. and Fratta, P. and Cox, G.A. and Thompson, L.M. and Finkbeiner, S. and Dardiotis, E. and Hornstein, E. and MacGowan, D.J.L. and Heiman-Patterson, T. and Hammell, M.G. and Patsopoulos, N.A. and Dubnau, J. and Nath, A. and Musunuri, R.L. and Evani, U.S. and Abhyankar, A. and Zody, M.C. and Kaye, J. and Wyman, S.K. and LeNail, A. and Lima, L. and Rothstein, J.D. and Svendsen, C.N. and Van Eyk, J.E. and Maragakis, N.J. and Kolb, S.J. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene, Neuron, 2018, 97, 6, 1268–1283
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To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
Type of material:Journal Article
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Keywords:Amyotrophic lateral sclerosis (ALS), Kinesin family member 5A (KIF5A), Cytoskeletal defects, Mutations, Neurodegenerative diseases