Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Franco Taroni Antonia Ratti Cinzia Gellera Philip van Damme 1 Wim Robberecht 1 Pietro Fratta Mario Sabatelli 2 Christian Lunetta Albert C. Ludolph Peter M. Andersen Jochen H. Weishaupt William Camu 3 John Q. Trojanowski Vivianna M. van Deerlin Robert H. Brown 4 Leonard H. Berg Jan H. Veldink Matthew B. Harms Jonathan D. Glass David J. Stone Pentti Tienari Vincenzo Silani Adriano Chiò 5 Christopher E. Shaw Bryan J. Traynor John E. Landers Aude Nicolas 6 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 Rheenen Natalie A. Murphy Joke J. F. A. Vugt Joshua T. Geiger Rick A. Spek Hannah A. Pliner Null Shankaracharya Bradley N. Smith Giuseppe Marangi Simon D. Topp Yevgeniya Abramzon Athina Soragia Gkazi John D. Eicher Aoife Kenna Italsgen Consortium Gabriele Mora Andrea Calvo 5 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 Lucia Corrado Margherita Capasso Luigi Ferrucci Genomic Translation Consortium Cristiane de Araujo Martins Moreno Sitharthan Kamalakaran David B. Goldstein Als Sequencing Consortium Aaron D. Gitler Tim Harris Richard M. Myers Nygc Als Consortium Hemali Phatnani Rajeeva Lochan Musunuri Uday Shankar Evani Avinash Abhyankar 7 Michael C. Zody Answer Als Foundation Julia Kaye Steven Finkbeiner Stacia K. Wyman Alex Lenail Leandro Lima 8, 9 Ernest Fraenkel Clive N. Svendsen Leslie M. Thompson Jennifer E. van Eyk James D. Berry Timothy M. Miller Stephen J. Kolb Merit Cudkowicz Emily Baxi Clinical Research Als Related Disorders Consortium Michael Benatar J. Paul Taylor 10, 11 Evadnie Rampersaud 10 Gang Wu Joanne Wuu Slagen Consortium Giuseppe Lauria Federico Verde Isabella Fogh Cinzia Tiloca Giacomo P. Comi Gianni Sorarù Cristina Cereda French Als Consortium Philippe Corcia 12 Hannu Laaksovirta Liisa Myllykangas Lilja Jansson Miko Valori John Ealing Hisham Hamdalla Sara Rollinson Stuart Pickering-Brown Richard W. Orrell Katie C. Sidle Andrea Malaspina John Hardy 13 Andrew B. Singleton Janel O. Johnson Sampath Arepalli Peter C. Sapp Diane Mckenna-Yasek Meraida Polak Seneshaw Asress Safa Al-Sarraj Andrew King 14 Claire Troakes 15 Caroline Vance Jacqueline Belleroche Frank Baas Anneloor L. M. A. ten Asbroek José Luis Muñoz-Blanco Dena G. Hernandez Jinhui Ding J. Raphael Gibbs 16 Sonja W. Scholz Mary Kay Floeter Roy H. Campbell Francesco Landi Robert Bowser Stefan M. Pulst John M. Ravits Daniel J. L. Macgowan Janine Kirby Erik P. Pioro Roger Pamphlett James Broach 17 Glenn Gerhard Travis L. Dunckley Christopher B. Brady Neil W. Kowall Juan C. Troncoso Isabelle Le Ber 6 Kevin Mouzat 18, 19 Serge Lumbroso 18, 19 Terry D. Heiman-Patterson Freya Kamel Ludo van den Bosch 1 Robert H. Baloh Tim M. Strom Thomas Meitinger 20, 21 Aleksey Shatunov Kristel R. van Eijk 22 Mamede Carvalho Maarten Kooyman Bas Middelkoop Matthieu Moisse Russell L. Mclaughlin Michael A. van Es Markus Weber 23 Kevin B. Boylan Marka van Blitterswijk Rosa Rademakers 24 Karen E. Morrison A. Nazli Basak Jesús S. Mora Vivian E. Drory Pamela J. Shaw Martin R. Turner Kevin Talbot Orla Hardiman 25 Kelly L. Williams Jennifer A. Fifita Garth A. Nicholson Ian P. Blair Guy A. Rouleau Jesús Esteban-Pérez Alberto Garc\'Ia-Redondo Ammar Al-Chalabi 26 Project Mine Als Sequencing Consortium Ekaterina Rogaeva 27 Lorne Zinman Lyle W. Ostrow Nicholas J. Maragakis Jeffrey D. Rothstein Zachary Simmons Johnathan Cooper-Knock Alexis Brice 28 Stephen A. Goutman Eva L. Feldman Summer B. Gibson
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.
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Franco Taroni, Antonia Ratti, Cinzia Gellera, Philip van Damme, Wim Robberecht, et al.. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron, Elsevier, 2018, 97 (6), pp.1268--1283.e6. ⟨10.1016/j.neuron.2018.02.027⟩. ⟨hal-02345947⟩

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