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.

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene / A. Nicolas, K.P. Kenna, A.E. Renton, N. Ticozzi, F. Faghri, R. Chia, J.A. Dominov, B.J. Kenna, M.A. Nalls, P. Keagle, A.M. Rivera, W. van Rheenen, N.A. Murphy, J.J.F.A. van Vugt, J.T. Geiger, R.A. Van der Spek, H.A. Pliner, N. Shankaracharya, B.N. Smith, G. Marangi, S.D. Topp, Y. Abramzon, A.S. Gkazi, J.D. Eicher, A. Kenna, G. Mora, A. Calvo, L. Mazzini, N. Riva, J. Mandrioli, C. Caponnetto, S. Battistini, P. Volanti, V. La Bella, F.L. Conforti, G. Borghero, S. Messina, I.L. Simone, F. Trojsi, F. Salvi, F.O. Logullo, S. D'Alfonso, L. Corrado, M. Capasso, L. Ferrucci, C.D.A.M. Moreno, S. Kamalakaran, D.B. Goldstein, A.D. Gitler, T. Harris, R.M. Myers, H. Phatnani, R.L. Musunuri, U.S. Evani, A. Abhyankar, M.C. Zody, J. Kaye, S. Finkbeiner, S.K. Wyman, A. Lenail, L. Lima, E. Fraenkel, C.N. Svendsen, L.M. Thompson, J.E. Van Eyk, J.D. Berry, T.M. Miller, S.J. Kolb, M. Cudkowicz, E. Baxi, M. Benatar, J.P. Taylor, E. Rampersaud, G. Wu, J. Wuu, G. Lauria, F. Verde, I. Fogh, C. Tiloca, G.P. Comi, G. Sorarù, C. Cereda, P. Corcia, H. Laaksovirta, L. Myllykangas, L. Jansson, M. Valori, J. Ealing, H. Hamdalla, S. Rollinson, S. Pickering-Brown, R.W. Orrell, K.C. Sidle, A. Malaspina, J. Hardy, A.B. Singleton, J.O. Johnson, S. Arepalli, P.C. Sapp, D. McKenna-Yasek, M. Polak, S. Asress, S. Al-Sarraj, A. King, C. Troakes, C. Vance, J. de Belleroche, F. Baas, A.L.M.A. Ten Asbroek, J.L. Muñoz-Blanco, D.G. Hernandez, J. Ding, J.R. Gibbs, S.W. Scholz, M.K. Floeter, R.H. Campbell, F. Landi, R. Bowser, S.M. Pulst, J.M. Ravits, D.J.L. Macgowan, J. Kirby, E.P. Pioro, R. Pamphlett, J. Broach, G. Gerhard, T.L. Dunckley, C.B. Brady, N.W. Kowall, J.C. Troncoso, I. Le Ber, K. Mouzat, S. Lumbroso, T.D. Heiman-Patterson, F. Kamel, L. Van Den Bosch, R.H. Baloh, T.M. Strom, T. Meitinger, A. Shatunov, K.R. Van Eijk, M. de Carvalho, M. Kooyman, B. Middelkoop, M. Moisse, R.L. Mclaughlin, M.A. Van Es, M. Weber, K.B. Boylan, M. Van Blitterswijk, R. Rademakers, K.E. Morrison, A.N. Basak, J.S. Mora, V.E. Drory, P.J. Shaw, M.R. Turner, K. Talbot, O. Hardiman, K.L. Williams, J.A. Fifita, G.A. Nicholson, I.P. Blair, G.A. Rouleau, J. Esteban-Pérez, A. García-Redondo, A. Al-Chalabi, E. Rogaeva, L. Zinman, L.W. Ostrow, N.J. Maragakis, J.D. Rothstein, Z. Simmons, J. Cooper-Knock, A. Brice, S.A. Goutman, E.L. Feldman, S.B. Gibson, F. Taroni, A. Ratti, C. Gellera, P. Van Damme, W. Robberecht, P. Fratta, M. Sabatelli, C. Lunetta, A.C. Ludolph, P.M. Andersen, J.H. Weishaupt, W. Camu, J.Q. Trojanowski, V.M. Van Deerlin, R.H. Brown, L.H. van den Berg, J.H. Veldink, M.B. Harms, J.D. Glass, D.J. Stone, P. Tienari, V. Silani, A. Chiò, C.E. Shaw, B.J. Traynor, J.E. Landers. - In: NEURON. - ISSN 0896-6273. - 97:6(2018 Mar 21), pp. 1268-1283. [10.1016/j.neuron.2018.02.027]

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

N. Ticozzi;G. Lauria;F. Verde;C. Tiloca;G.P. Comi;A. Ratti;V. Silani;
2018

Abstract

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.
ALS; GWAS; KIF5A; WES; WGS; axonal transport; cargo
Settore MED/26 - Neurologia
Settore MED/03 - Genetica Medica
Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica
Settore BIO/18 - Genetica
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/566965
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