Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Giuseppe Marangi, Mario Sabatelli, Marcella Zollino, Francesco Landi, Giandomenico Logroscino, Monica Capasso, Luigi Mosca, Alfonso Fasano, Amelia Conte, Marco Luigetti, Serena Lattante, Sandra D'Alfonso, Giovanni Siciliano, Vanna Maria Valori, Aude Nicolas, Kevin P. Kenna, Alan E. Renton, Nicola Ticozzi, Faraz Faghri, Ruth ChiaJanice 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, Shankaracharya, Bradley N. Smith, Simon D. Topp, Yevgeniya Abramzon, Athina Soragia Gkazi, John D. Eicher, Aoife Kenna, Francesco O. Logullo, Isabella L. Simone, Fabrizio Salvi, Giuseppe Borghero, Margherita Capasso, Claudia Caponnetto, Francesca L. Conforti, Gabriele Mora, Christian Lunetta, Nilo Riva, Paolo Volanti, Jessica Mandrioli, Francesca Trojsi, Vincenzo La Bella, Stefania Battistini, Andrea Calvo, Letizia Mazzini, Sonia Messina, Lucia Corrado, Luigi Ferrucci, Matthew B. Harms, David B. Goldstein, Stephen A. Goutman, Zachary Simmons, Timothy M. Miller, Robert H. Baloh, Summer B. Gibson, Cristiane De Araujo Martins Moreno, Sitharthan Kamalakaran, Robert H. Brown, Aaron D. Gitler, Jonathan D. Glass, Tim Harris, Diane Mckenna-Yasek, Richard M. Myers, Stefan M. Pulst, John M. Ravits, Guy A. Rouleau, Peter C. Sapp, Hemali Phatnani, James Broach, Vivianna M. Van Deerlin, Ernest Fraenkel, Lyle W. Ostrow, Frank Baas, James D. Berry, Andrea Malaspina, Pietro Fratta, Leslie M. Thompson, Steven Finkbeiner, Daniel J.L. Macgowan, Rajeeva Lochan Musunuri, Uday Shankar Evani, Avinash Abhyankar, Michael C. Zody, Julia Kaye, Stacia K. Wyman, Alex Lenail, Leandro Lima, Jeffrey D. Rothstein, Clive N. Svendsen, Jennifer E. Van Eyk, Nicholas J. Maragakis, Stephen J. Kolb, Merit Cudkowicz, Emily Baxi, Michael Benatar, J. Paul Taylor, Gang Wu, Evadnie Rampersaud, Joanne Wuu, Rosa Rademakers, Erik P. Pioro, Vincenzo Silani, Cinzia Gellera, Antonia Ratti, Franco Taroni, Giuseppe Lauria, Federico Verde, Isabella Fogh, Cinzia Tiloca, Giacomo P. Comi, Gianni Sorarù, Cristina Cereda, William Camu, Kevin Mouzat, Serge Lumbroso, 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, John Hardy, Andrew B. Singleton, Janel O. Johnson, Sampath Arepalli, Meraida Polak, Seneshaw Asress, Safa Al-Sarraj, Andrew King, Claire Troakes, Caroline Vance, Jacqueline De Belleroche, 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, Robert Bowser, Janine Kirby, Roger Pamphlett, Glenn Gerhard, Travis L. Dunckley, Christopher B. Brady, Neil W. Kowall, Juan C. Troncoso, Isabelle Le Ber, Terry D. Heiman-Patterson, Freya Kamel, Ludo Van Den Bosch, 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, 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, Jesús Esteban-Pérez, Alberto García-Redondo, Ammar Al-Chalabi, Peter M. Andersen, Johnathan Cooper-Knock, John E. Landers, Wim Robberecht, Philip Van Damme, Leonard H. Van Den Berg, Jan H. Veldink, Ekaterina Rogaeva, Lorne Zinman, Alexis Brice, Eva L. Feldman, Albert C. Ludolph, Jochen H. Weishaupt, John Q. Trojanowski, David J. Stone, Pentti Tienari, Adriano Chiò, Christopher E. Shaw, Bryan J. Traynor

Risultato della ricerca: Contributo in rivistaArticolo in rivista

184 Citazioni (Scopus)

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. Using a large-scale genome-wide association study and exome sequencing, we identified KIF5A as a novel gene associated with ALS. Our data broaden the phenotype resulting from mutations in KIF5A and highlight the importance of cytoskeletal defects in the pathogenesis of ALS.
Lingua originaleEnglish
pagine (da-a)1268-1283.e6
RivistaNeuron
Volume2018
DOI
Stato di pubblicazionePubblicato - 2018

Keywords

  • ALS
  • Adult
  • Aged
  • Aged, 80 and over
  • Amino Acid Sequence
  • Amyotrophic Lateral Sclerosis
  • Cohort Studies
  • Female
  • GWAS
  • Genome-Wide Association Study
  • Humans
  • KIF5A
  • Kinesin
  • Loss of Function Mutation
  • Male
  • Middle Aged
  • WES
  • WGS
  • Young Adult
  • axonal transport
  • cargo

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