Genome-wide analyses identify KIF5A as a novel ALS gene

• Verfasst von: Nicolas, Aude [VerfasserIn]
• Verfasst von: Weishaupt, Jochen H. [VerfasserIn]
• Titel: Genome-wide analyses identify KIF5A as a novel ALS gene
• Verf.angabe: authors: 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. Smith, Giuseppe Marangi, Simon D. Topp, Yevgeniya Abramzon, Athina Soragia Gkazi, John D. Eicher, Aoife Kenna, ITALSGEN Consortium, 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, Lucia Corrado, Margherita Capasso, Luigi Ferrucci, Genomic Translation for ALS Care (GTAC) 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, Michael C. Zody, Answer ALS Foundation, Julia Kaye, Steven Finkbeiner, Stacia K. Wyman, Alex LeNail, Leandro Lima, 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 in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, Michael Benatar, J. Paul Taylor, Evadnie Rampersaud, 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, 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, Andrew B. Singleton, Janel O. Johnson, Sampath Arepalli, Peter C. Sapp, Diane McKenna-Yasek, Meraida Polak, Seneshaw Asress, Safa Al-Sarraj, Andrew King, Claire Troakes, Caroline Vance, Jacqueline de Belleroche, Frank Baas, Anneloor L. M. A. Ten Asbroek, José Luis Muñoz-Blanco, Dena G. Hernandez, Jinhui Ding, J. Raphael Gibbs, 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, Glenn Gerhard, Travis L. Dunckley, Christopher B. Brady, Neil W. Kowall, Juan C. Troncoso, Isabelle Le Ber, Kevin Mouzat, Serge Lumbroso, Terry D. Heiman-Patterson, Freya Kamel, Ludo Van Den Bosch, Robert H. Baloh, Tim M. Strom, Thomas Meitinger, Aleksey Shatunov, Kristel R. Van Eijk, Mamede de Carvalho, Maarten Kooyman, Bas Middelkoop, Matthieu Moisse, Russell L. McLaughlin, Michael A. Van Es, Markus Weber, Kevin B. Boylan, Marka Van Blitterswijk, Rosa Rademakers, Karen E. Morrison, A. Nazli Basak, Jesús S. Mora, Vivian E. Drory, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Orla Hardiman, Kelly L. Williams, Jennifer A. Fifita, Garth A. Nicholson, Ian P. Blair, Guy A. Rouleau, Jesús Esteban-Pérez, Alberto García-Redondo, Ammar Al-Chalabi, Project MinE ALS Sequencing Consortium, Ekaterina Rogaeva, Lorne Zinman, Lyle W. Ostrow, Nicholas J. Maragakis, Jeffrey D. Rothstein, Zachary Simmons, Johnathan Cooper-Knock, Alexis Brice, Stephen A. Goutman, Eva L. Feldman, Summer B. Gibson, Franco Taroni, Antonia Ratti, Cinzia Gellera, Philip Van Damme, Wim Robberecht, Pietro Fratta, Mario Sabatelli, Christian Lunetta, Albert C. Ludolph, Peter M. Andersen, Jochen H. Weishaupt, William Camu, John Q. Trojanowski, Vivianna M. Van Deerlin, Robert H. Brown, Leonard H. van den Berg, Jan H. Veldink, Matthew B. Harms, Jonathan D. Glass, David J. Stone, Pentti Tienari, Vincenzo Silani, Adriano Chiò, Christopher E. Shaw, Bryan J. Traynor, John E. Landers
• E-Jahr: 2018
• Jahr: 21 March 2018
• Umfang: 22 S.
• Teil: volume:97
• Teil: year:2018
• Teil: number:6
• Teil: pages:1268-1283.e6
• Teil: extent:22
• Fussnoten: Gesehen am 16.06.2021
• Titel Quelle: Enthalten in: Neuron
• Ort Quelle: [Cambridge, Mass.] : Cell Press, 1988
• Jahr Quelle: 2018
• Band/Heft Quelle: 97(2018), 6, Seite 1268-1283.e6
• ISSN Quelle: 1097-4199
• DOI: doi:10.1016/j.neuron.2018.02.027
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Adult
• Sach-SW: Aged
• Sach-SW: Aged, 80 and over
• Sach-SW: ALS
• Sach-SW: Amino Acid Sequence
• Sach-SW: Amyotrophic Lateral Sclerosis
• Sach-SW: axonal transport
• Sach-SW: cargo
• Sach-SW: Cohort Studies
• Sach-SW: Female
• Sach-SW: Genome-Wide Association Study
• Sach-SW: GWAS
• Sach-SW: Humans
• Sach-SW: KIF5A
• Sach-SW: Kinesin
• Sach-SW: Loss of Function Mutation
• Sach-SW: Male
• Sach-SW: Middle Aged
• Sach-SW: WES
• Sach-SW: WGS
• Sach-SW: Young Adult
• K10plus-PPN: 1760573574

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.