Detalhes do Documento

Genome-wide analyses identify KIF5A as a novel ALS gene

Autor(es): Nicolas, Aude ; Kenna, Kevin P. ; Renton, Alan E. ; Ticozzi, Nicola ; Faghri, Faraz ; Chia, Ruth ; Dominov, Janice A. ; Kenna, Brendan J. ; Nalls, Mike A. ; Keagle, Pamela ; Rivera, Alberto M. ; Couratier, Philippe ; Murphy, Natalie A. ; Pardina, Jesus Mora ; Mill, Jonathan ; Canosa, Antonio ; Ealing, John ; Johnson, Janel O. ; Brice, Alexis ; Tiloca, Cinzia ; Sims, Katherine B. ; Monsurrò, Maria Rosaria ; Moisse, Matthieu ; Cereda, Cristina ; Zatz, Mayana ; van den Berg, Leonard H. ; Pulit, Sara ; Filosto, Massimiliano ; Topp, Simon D. ; Malaspina, Andrea ; Pliner, Hannah A. ; Jackson, Carlayne ; Taylor, J. Paul ; Gotkine, Marc ; Gkazi, Athina Soragia ; Fraenkel, Ernest ; Mandrioli, Jessica ; Harris, Tim ; Van Blitterswijk, Marka ; LeNail, Alex ; Cooley, Anne ; Nicholson, Garth A. ; Cau, Tea B. ; Danel, Véronique ; Kaye, Julia ; Miller, Timothy M. ; Benatar, Michael ; Wu, Gang ; Femiano, Cinzia ; Bernard, Emilien ; Van Deerlin, Vivianna M. ; Tedeschi, Gioacchino ; Dubnau, Joshua ; Milia, Antonio ; Floris, Gianluca ; Brown, Robert H. ; Al-Sarraj, Safa ; Fratta, Pietro ; Turner, Martin R. ; Patsopoulos, Nikolaos A. ; Veldink, Jan H. ; Salvi, Fabrizio ; Murru, Maria Rita ; Trivedi, Jaya ; Marinou, Kalliopi ; Finkbeiner, Steven ; Tanel, Raffaella ; Troncoso, Juan C. ; Parish, Leslie D. ; Kowall, Neil W. ; Robberecht, Wim ; Spataro, Rossella ; Barberis, Marco ; Gwathmey, Kelly ; Lauria, Giuseppe ; Landi, Francesco ; Asress, Seneshaw ; Boylan, Kevin B. ; Guy, Nathalie ; Chung, Wendy K. ; Tienari, Pentti ; Corcia, Philippe ; De Marchi, Fabiola ; Nath, Avindra ; Van Eyk, Jenny ; Carrera, Paola ; Kolb, Stephen J. ; Staropoli, John F. ; Trojsi, Francesca ; Taroni, Franco ; Sherman, Alexander ; Fini, Nicola ; Pal, Suvankar ; Kiernan, Matthew ; Van Es, Michael A. ; Messina, Sonia ; Rademakers, Rosa ; Vourch, Patrick ; Shankaracharya ; Fasano, Antonio ; Xin, Winnie W. ; Middelkoop, Bas ; Rouleau, Guy A. ; Ostrow, Lyle W. ; Caredda, Carla ; Corongiu, Daniela ; Burns, Ted ; Gitler, Aaron D. ; Sidle, Katie C. ; Corti, Stefania ; Heiman-Patterson, Terry D. ; Orrell, Richard W. ; Day-Williams, Aaron G. ; Muñoz-Blanco, José Luis ; Ding, Jinhui ; Sapp, Peter C. ; Lu, Yi-Fan ; Wang, Quanli ; Caponnetto, Claudia ; Cuccu, Stefania ; Bruijn, Lucie ; Arepalli, Sampath ; Pulst, Stefan M. ; Manousakis, George ; Rollinson, Sara ; Myllykangas, Liisa ; Origone, Paola ; Kirby, Janine ; Khan, Shaida ; Zinman, Lorne ; Barohn, Richard ; Arosio, Alessandro ; Fogh, Isabella ; Clayman, Christine ; Heckmann, Jeannine ; Restagno, Gabriella ; Ferrucci, Luigi ; Sideri, Riccardo ; Kamalakaran, Sitharthan ; Ludolph, Albert C. ; Campbell, Roy H. ; Luigetti, Marco ; Lee, Edward B. ; Mosca, Lorena ; Wuu, Joanne ; Tazelaar, Gijs ; Petrucci, Antonio ; Ortu, Enzo ; Bertolin, Cinzia ; Van der Spek, Rick A. ; Stone, David J. ; Brady, Christopher B. ; Andersen, Peter M. ; Fuda, Giuseppe ; Marrali, Giuseppe ; Mora, Gabriele ; Thompson, Leslie M. ; Van Eyk, Jennifer E. ; Maragakis, Nicholas J. ; Chiò, Adriano ; Rampersaud, Evadnie ; Iacoangeli, Alfredo ; Levy, Shawn E. ; Lunetta, Christian ; Lattante, Serena ; Hornstein, Eran ; Lagrange, Emmeline ; Casale, Federico ; Hide, Winston ; Ravits, John M. ; Singleton, Andrew B. ; Marrosu, Francesco ; Raphael, Alya R. ; Pinto, Susana ; Kenna, Aoife ; Ossola, Irene ; Shaw, Christopher E. ; Hayes, Sebastian D. ; Simpson, Ericka ; Krueger, Brian J. ; Caress, James ; Fifita, Jennifer A. ; Newhouse, Stephen ; Zollino, Marcella ; Myers, Richard M. ; Landers, John E. ; Svendsen, Clive N. ; Comi, Giacomo P. ; Wimbish, Jack R. ; Calvo, Andrea ; Hussain, Sumaira ; Couthouis, Julien ; Cooper, Gregory M. ; Han, Yujun ; Goutman, Stephen A. ; Vance, Caroline ; Hamdalla, Hisham ; Valori, Miko ; Meitinger, Thomas ; Chesi, Alessandra ; Hardiman, Orla ; Allen, Andrew S. ; Dion, Patrick A. ; Wang, Leo ; Cooper-Knock, Johnathan ; Statland, Jeffrey ; Geiger, Joshua T. ; Harms, Matthew B. ; Troakes, Claire ; Dekker, Annelot ; Querin, Giorgia ; Redondo, Alberto Garcia ; Sareen, Dhruv ; Boone, Braden E. ; Costantino, Emanuela ; Besson, Gérard ; Ricci, Claudia ; McLaughlin, Russell L. ; Züchner, Stephan ; Van Den Bosch, Ludo ; Baas, Frank ; Dunckley, Travis L. ; Basak, A. Nazli ; Traynor, Bryan J. ; Baloh, Robert H. ; Pensato, Viviana ; Abhyankar, Avinash ; Cammarosano, Stefania ; Jones, Angela L. ; Marangi, Giuseppe ; Pamphlett, Roger ; Brunetti, Maura ; Loi, Daniela ; Weishaupt, Jochen H. ; Drory, Vivian E. ; Cannas, Antonino ; Blair, Ian P. ; Camu, William ; Borghero, Giuseppe ; Waite, Lindsay L. ; Trojanowski, John Q. ; Appel, Stanley H. ; Colletti, Tiziana ; Battistini, Stefania ; Pugliatti, Maura ; Zody, Michael C. ; Laaksovirta, Hannu ; Morrison, Karen E. ; Capasso, Margherita ; Pirisi, Angelo ; Berry, James D. ; Wallace, Marielle ; Ren, Zhong ; Santarelli, Marialuisa ; Hardy, John ; Sorarù, Gianni ; Musunuri, Rajeeva Lochan ; Peverelli, Silvia ; MacGowan, Daniel J.L. ; Bartolomei, Ilaria ; Melis, Maurizio ; Mouzat, Kevin ; Arcila-Londono, Ximena ; Broach, James R. ; So, Yuen ; Moglia, Cristina ; Cox, Gregory A. ; Bowser, Robert ; Goldstein, David B. ; Hammell, Molly G. ; King, Andrew ; Lacomis, David ; Talbot, Kevin ; McCauley, Jacob ; Maniatis, Tom ; van Rheenen, Wouter ; Meininger, Vincent ; Giannini, Fabio ; Pani, Carla ; Scholz, Sonja W. ; Pioro, Erik P. ; van Vugt, Joke J.F.A. ; Phatnani, Hemali ; Bauer, Denis C. ; Van Damme, Philip ; Keebler, Jonathan ; Wyman, Stacia K. ; Cirulli, Elizabeth T. ; Esteban-Pérez, Jesús ; Baxi, Emily ; Swenson, Andrea ; Logroscino, Giancarlo ; D’Alfonso, Sandra ; Gerhard, Glenn ; Clavelou, Pierre ; Piras, Valeria ; Glass, Jonathan D. ; ten Asbroek, Anneloor L.M.A. ; Smith, Bradley N. ; Elman, Lauren ; Petrovski, Slavé ; Eicher, John D. ; Silani, Vincenzo ; La Bella, Vincenzo ; Shatunov, Aleksey ; Rogaeva, Ekaterina ; Cudkowicz, Merit ; Corrado, Lucia ; McMillan, Corey ; Castellotti, Barbara ; Poletti, Barbara ; Zhang, Jinghui ; Moreno, Cristiane de Araujo Martins ; Lima, Leandro ; Tranquilli, Stefania ; Al-Chalabi, Ammar ; Del Bo, Roberto ; Al Kheifat, Ahmad ; Mandich, Paola ; Neto, Miguel Mitne ; Shneider, Neil A. ; Benigni, Michele ; Lemasson, Gwendal ; Conforti, Francesca L. ; Walk, David ; Corbo, Massimo ; Penco, Silvana ; Katz, Jonathan ; Puddu, Roberta ; Logullo, Francesco O. ; Tremolizzo, Lucio ; Piccirillo, Giovanni ; Ticca, Anna ; Gagliardi, Stella ; Inghilleri, Maurizio ; Van Eijk, Kristel R. ; Gellera, Cinzia ; Conte, Amelia ; Mora, Jesús S. ; Weber, Markus ; Ilardi, Antonio ; Simmons, Zachary ; Sabatelli, Mario ; Abramzon, Yevgeniya ; Floeter, Mary Kay ; Williams, Kelly L. ; Cavallaro, Sebastiano ; Ferrarese, Carlo ; Pinter, Giuseppe Lauria ; Strom, Tim M. ; Manera, Umberto ; Carulli, John P. ; Grassano, Maurizio ; Mazzini, Letizia ; Marrosu, Maria Giovanna ; Gibson, Summer B. ; Maiser, Samuel ; Kwan, Justin ; Verde, Federico ; Shaw, Pamela J. ; Twine, Natalie A. ; Polak, Meraida ; Hernandez, Dena G. ; García-Redondo, Alberto ; Ratti, Antonia ; Siciliano, Gabriele ; Simone, Isabella ; Chandran, Siddharthan ; Sproviero, William ; Zaitlen, Noah ; Penny, Michelle ; Volanti, Paolo ; Feldman, Eva L. ; McKenna-Yasek, Diane ; Pisano, Fabrizio ; Occhineri, Patrizia ; Jansson, Lilja ; Mancardi, Gianluigi ; Evani, Uday Shankar ; de Belleroche, Jacqueline ; Lasseigne, Brittany N. ; Schule, Rebecca ; Kamel, Freya ; Ceroni, Mauro ; Bedlack, Richard S. ; Rothstein, Jeffrey D. ; Le Ber, Isabelle ; Colombrita, Claudia ; Kooyman, Maarten ; Dardiotis, Efthimios ; Gibbs, J. Raphael ; Carvalho, Mamede ; Jenkins, Liberty ; Lumbroso, Serge ; Riva, Nilo ; Maderna, Luca ; Pickering-Brown, Stuart

Data: 2018

Identificador Persistente: http://hdl.handle.net/10451/48231

Origem: Repositório da Universidade de Lisboa

Assunto(s): ALS; GWAS; KIF5A; WES; WGS; Axonal transport; Cargo


Descrição

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.

Tipo de Documento Artigo científico
Idioma Inglês
Contribuidor(es) Repositório Científico de Acesso Aberto da ULisboa
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