A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD
Alan E Renton, Elisa Majounie, Adrian Waite, Javier Simón-Sánchez, Sara Rollinson, J Raphael Gibbs, Jennifer C Schymick, Hannu Laaksovirta, John C van Swieten, Liisa Myllykangas, Hannu Kalimo, Anders Paetau, Yevgeniya Abramzon, Anne M Remes, Alice Kaganovich, Sonja W Scholz, Jamie Duckworth, Jinhui Ding, Daniel W Harmer, Dena G Hernandez, Janel O Johnson, Kin Mok, Mina Ryten, Danyah Trabzuni, Rita J Guerreiro, Richard W Orrell, James Neal, Alex Murray, Justin Pearson, Iris E Jansen, David Sondervan, Harro Seelaar, Derek Blake, Kate Young, Nicola Halliwell, Janis Bennion Callister, Greg Toulson, Anna Richardson, Alex Gerhard, Julie Snowden, David Mann, David Neary, Michael A Nalls, Terhi Peuralinna, Lilja Jansson, Veli-Matti Isoviita, Anna-Lotta Kaivorinne, Maarit Hölttä-Vuori, Elina Ikonen, Raimo Sulkava, Michael Benatar, Joanne Wuu, Adriano Chiò, Gabriella Restagno, Giuseppe Borghero, Mario Sabatelli, ITALSGEN Consortium, David Heckerman, Ekaterina Rogaeva, Lorne Zinman, Jeffrey D Rothstein, Michael Sendtner, Carsten Drepper, Evan E Eichler, Can Alkan, Ziedulla Abdullaev, Svetlana D Pack, Amalia Dutra, Evgenia Pak, John Hardy, Andrew Singleton, Nigel M Williams, Peter Heutink, Stuart Pickering-Brown, Huw R Morris, Pentti J Tienari, Bryan J Traynor, Andrea Calvo, Stefania Cammarosano, Cristina Moglia, Antonio Canosa, Sara Gallo, Maura Brunetti, Irene Ossola, Gabriele Mora, Kalliopi Marinou, Laura Papetti, Amelia Conte, Marco Luigetti, Vincenzo La Bella, Rossella Spataro, Tiziana Colletti, Stefania Battistini, Fabio Giannini, Claudia Ricci, Claudia Caponnetto, Gianluigi Mancardi, Paola Mandich, Fabrizio Salvi, Ilaria Bartolomei, Jessica Mandrioli, Patrizia Sola, Massimo Corbo, Christian Lunetta, Silvana Penco, Maria Rosaria Monsurrò, Gioacchino Tedeschi, Francesca Luisa Conforti, Paolo Volanti, Gianluca Floris, Antonino Cannas, Valeria Piras, Maria Rita Murru, Maria Giovanna Marrosu, Maura Pugliatti, Anna Ticca, Isabella Simone, Giancarlo Logroscino, Alan E Renton, Elisa Majounie, Adrian Waite, Javier Simón-Sánchez, Sara Rollinson, J Raphael Gibbs, Jennifer C Schymick, Hannu Laaksovirta, John C van Swieten, Liisa Myllykangas, Hannu Kalimo, Anders Paetau, Yevgeniya Abramzon, Anne M Remes, Alice Kaganovich, Sonja W Scholz, Jamie Duckworth, Jinhui Ding, Daniel W Harmer, Dena G Hernandez, Janel O Johnson, Kin Mok, Mina Ryten, Danyah Trabzuni, Rita J Guerreiro, Richard W Orrell, James Neal, Alex Murray, Justin Pearson, Iris E Jansen, David Sondervan, Harro Seelaar, Derek Blake, Kate Young, Nicola Halliwell, Janis Bennion Callister, Greg Toulson, Anna Richardson, Alex Gerhard, Julie Snowden, David Mann, David Neary, Michael A Nalls, Terhi Peuralinna, Lilja Jansson, Veli-Matti Isoviita, Anna-Lotta Kaivorinne, Maarit Hölttä-Vuori, Elina Ikonen, Raimo Sulkava, Michael Benatar, Joanne Wuu, Adriano Chiò, Gabriella Restagno, Giuseppe Borghero, Mario Sabatelli, ITALSGEN Consortium, David Heckerman, Ekaterina Rogaeva, Lorne Zinman, Jeffrey D Rothstein, Michael Sendtner, Carsten Drepper, Evan E Eichler, Can Alkan, Ziedulla Abdullaev, Svetlana D Pack, Amalia Dutra, Evgenia Pak, John Hardy, Andrew Singleton, Nigel M Williams, Peter Heutink, Stuart Pickering-Brown, Huw R Morris, Pentti J Tienari, Bryan J Traynor, Andrea Calvo, Stefania Cammarosano, Cristina Moglia, Antonio Canosa, Sara Gallo, Maura Brunetti, Irene Ossola, Gabriele Mora, Kalliopi Marinou, Laura Papetti, Amelia Conte, Marco Luigetti, Vincenzo La Bella, Rossella Spataro, Tiziana Colletti, Stefania Battistini, Fabio Giannini, Claudia Ricci, Claudia Caponnetto, Gianluigi Mancardi, Paola Mandich, Fabrizio Salvi, Ilaria Bartolomei, Jessica Mandrioli, Patrizia Sola, Massimo Corbo, Christian Lunetta, Silvana Penco, Maria Rosaria Monsurrò, Gioacchino Tedeschi, Francesca Luisa Conforti, Paolo Volanti, Gianluca Floris, Antonino Cannas, Valeria Piras, Maria Rita Murru, Maria Giovanna Marrosu, Maura Pugliatti, Anna Ticca, Isabella Simone, Giancarlo Logroscino
Abstract
The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.
Copyright © 2011 Elsevier Inc. All rights reserved.
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Source: PubMed