Paper
Document
Download
Flag content
0

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Authors
Franco Taroni,Antonia Ratti
Cinzia Gellera,Philip Damme,Pamela Shaw,Pietro Fratta,Mario Sabatelli,Albert Ludolph,Peter Andersen,Jochen Weishaupt,William Sproviero,John Trojanowski,Vivianna Deerlin,Robert Brown,Leonard Berg,Jan Veldink,Matthew Kiernan,Jonathan Mill,David Stone,Pentti Tienari,Vincenzo Silani,Adriano Chiò,Christopher Shaw,Bryan Traynor,John Landers,Aude Nicolas,Kevin Talbot,Alan Renton,Nicola Ticozzi,Faraz Faghri,Ruth Chia,Janice Dominov,Brendan Kenna,Mike Nalls,Alberto Rivera,Wouter Rheenen,Natalie Twine,Joke Vugt,Joshua Geiger,Rick Spek,Hannah Pliner,Null Shankaracharya,Bradley Smith,Giuseppe Marangi,Simon Topp,Yevgeniya Abramzon,Soragia Gkazi,John Eicher,Aoife Kenna,ITALSGEN Consortium,Gabriele Mora,Andrea Calvo,Letizia Mazzini,Nilo Riva,Jessica Mandrioli,Claudia Caponnetto,Stefania Battistini,Paolo Volanti,Vincenzo Bella,F. Conforti,Giuseppe Borghero,Sonia Messina,Isabella Simone,Francesca Trojsi,Fabrizio Salvi,Francesco Logullo,Sandra D’Alfonso,Lucia Corrado,Margherita Capasso,Luigi Ferrucci,Genomic Consortium,Cristiane Moreno,Sitharthan Kamalakaran,David Goldstein,Als Consortium,Aaron Gitler,Tim Harris,R Myers,NYGC Consortium,Hemali Phatnani,Rajeeva Musunuri,Uday Evani,Avinash Abhyankar,Michael Zody,Answer Foundation,Julia Kaye,Steven Finkbeiner,Stacia Wyman,Alex Lenail,Leandro Lima,Ernest Fraenkel,Clive Svendsen,Leslie Thompson,Jennifer Eyk,James Berry,Timothy Miller,Stephen Kolb,Merit Cudkowicz,Emily Baxi,Clinical Als,Related Consortium,Michael Benatar,J. Taylor,Evadnie Rampersaud,Gang Wu,Joanne Wuu,SLAGEN Consortium,Giuseppe Lauria,Federico Verde,Isabella Fogh,Giacomo Comi,Gianni Sorarù,Cristina Cereda,French Consortium,Philippe Corcia,Hannu Laaksovirta,Liisa Myllykangas,Lilja Jansson,Miko Valori,John Ealing,Hisham Hamdalla,Sara Rollinson,Stuart Pickering‐Brown,Richard Orrell,Katie Sidle,Andrea Malaspina,John Hardy,Maria Cotelli,Janel Johnson,Henk Berendse,Peter Sapp,Diane McKenna‐Yasek,Meraida Polak,Seneshaw Asress,Safa Al‐Sarraj,Andrew King,Claire Troakes,Caroline Vance,Jacqueline Belleroche,Frank Baas,Anneloor Asbroek,José Muñoz‐Blanco,Dena Hernández,Jinhui Ding,J. Gibbs,Sonja Scholz,Mary Floeter,Roy Campbell,Francesco Landi,Robert Bowser,Stefan Pulst,John Ravits,Daniel MacGowan,Janine Kirby,Roger Pamphlett,James Broach,Glenn Gerhard,Travis Dunckley,Christopher Brady,Neil Kowall,Juan Troncoso,Isabelle Ber,Michael Sendtner,Serge Lumbroso,Terry Heiman‐Patterson,Freya Kamel,Ludo Bosch,Robert Baloh,Tim Strom,Thomas Meitinger,Aleksey Shatunov,Kelly Williams,Mamede Carvalho,Maarten Kooyman,Bas Middelkoop,Matthieu Moisse,Russell McLaughlin,Michael Es,Markus Weber,Khrista Boylan,Marka Blitterswijk,Karen Morrison,A. Başak,Jesús Mora,Vivian Drory,Martin Turner,Orla Hardiman,Jennifer Fifita,Garth Nicholson,Ian Blair,Guy Rouleau,Jesús Esteban‐Pérez,Alberto García‐Redondo,Ammar Al‐Chalabi,Project Consortium,Ekaterina Rogaeva,Lorne Zinman,Lyle Ostrow,Nicholas Maragakis,Jeffrey Statland,Zachary Simmons,Johnathan Cooper‐Knock,Alexis Brice,Stephen Goutman,Eva Feldman
+203 authors
,Athina Gkazi
Journal
Published
Mar 1, 2018
Show more
Save
TipTip
Document
Download
Flag content
0
TipTip
Save
Document
Download
Flag content

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.

Paper PDF

This paper's license is marked as closed access or non-commercial and cannot be viewed on ResearchHub. Visit the paper's external site.