Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

ITALSGEN consortium, Aude Nicolas, Kevin P Kenna, Alan E Renton, Nicola Ticozzi, Faraz Faghri, Ruth Chia, Janice A Dominov, Brendan J Kenna, Mike A Nalls, Pamela Keagle, Alberto M Rivera, Wouter van Rheenen, Natalie A Murphy, Joke J F A van Vugt, Joshua T Geiger, Rick A Van der Spek, Hannah A Pliner, null Shankaracharya, Bradley N SmithGiuseppe Marangi, Simon D Topp, Yevgeniya Abramzon, Athina Soragia Gkazi, John D Eicher, Aoife Kenna, Gabriele Mora, Andrea Calvo, Letizia Mazzini, Nilo Riva, Jessica Mandrioli, Claudia Caponnetto, Stefania Battistini, Paolo Volanti, Vincenzo La Bella, Francesca L Conforti, Giuseppe Borghero, Sonia Messina, Isabella L Simone, Francesca Trojsi, Fabrizio Salvi, Francesco O Logullo, Sandra D'Alfonso, Giuseppe Lauria, Cinzia Tiloca, Giacomo P Comi, Cristina Cereda, Franco Taroni, Antonia Ratti, Cinzia Gellera, Vincenzo Silani

Research output: Contribution to journalArticle


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.
Original languageItalian
Pages (from-to)1268-1283.e6
Issue number6
Publication statusPublished - Mar 21 2018

Cite this

consortium, ITALSGEN., Nicolas, A., Kenna, K. P., Renton, A. E., Ticozzi, N., Faghri, F., Chia, R., Dominov, J. A., Kenna, B. J., Nalls, M. A., Keagle, P., Rivera, A. M., van Rheenen, W., Murphy, N. A., van Vugt, J. J. F. A., Geiger, J. T., Van der Spek, R. A., Pliner, H. A., Shankaracharya, N., ... Silani, V. (2018). Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron, 97(6), 1268-1283.e6.