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. HernandezJanel 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 G Benatar, Joanne Wuu, Adriano Chiò, Gabriella Restagno, Giuseppe Borghero, Mario Sabatelli, 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

Research output: Contribution to journalArticle

2223 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)257-268
Number of pages12
JournalNeuron
Volume72
Issue number2
DOIs
StatePublished - Oct 20 2011

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Neurodegenerative Diseases
Haplotypes
Chromosomes
Dominant Genes
Finland
Introns
Population
Mutation
Genes
Frontotemporal Dementia With Motor Neuron Disease

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Renton, A. E., Majounie, E., Waite, A., Simón-Sánchez, J., Rollinson, S., Gibbs, J. R., ... Traynor, B. J. (2011). A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron, 72(2), 257-268. https://doi.org/10.1016/j.neuron.2011.09.010

A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. / Renton, Alan E.; Majounie, Elisa; Waite, Adrian; Simón-Sánchez, Javier; Rollinson, Sara; Gibbs, J. Raphael; Schymick, Jennifer C.; Laaksovirta, Hannu; van Swieten, John C.; Myllykangas, Liisa; Kalimo, Hannu; Paetau, Anders; Abramzon, Yevgeniya; Remes, Anne M.; Kaganovich, Alice; Scholz, Sonja W.; Duckworth, Jamie; Ding, Jinhui; Harmer, Daniel W.; Hernandez, Dena G.; Johnson, Janel O.; Mok, Kin; Ryten, Mina; Trabzuni, Danyah; Guerreiro, Rita J.; Orrell, Richard W.; Neal, James; Murray, Alex; Pearson, Justin; Jansen, Iris E.; Sondervan, David; Seelaar, Harro; Blake, Derek; Young, Kate; Halliwell, Nicola; Callister, Janis Bennion; Toulson, Greg; Richardson, Anna; Gerhard, Alex; Snowden, Julie; Mann, David; Neary, David; Nalls, Michael A.; Peuralinna, Terhi; Jansson, Lilja; Isoviita, Veli Matti; Kaivorinne, Anna Lotta; Hölttä-Vuori, Maarit; Ikonen, Elina; Sulkava, Raimo; Benatar, Michael G; Wuu, Joanne; Chiò, Adriano; Restagno, Gabriella; Borghero, Giuseppe; Sabatelli, Mario; Heckerman, David; Rogaeva, Ekaterina; Zinman, Lorne; Rothstein, Jeffrey D.; Sendtner, Michael; Drepper, Carsten; Eichler, Evan E.; Alkan, Can; Abdullaev, Ziedulla; Pack, Svetlana D.; Dutra, Amalia; Pak, Evgenia; Hardy, John; Singleton, Andrew; Williams, Nigel M.; Heutink, Peter; Pickering-Brown, Stuart; Morris, Huw R.; Tienari, Pentti J.; Traynor, Bryan J.

In: Neuron, Vol. 72, No. 2, 20.10.2011, p. 257-268.

Research output: Contribution to journalArticle

Renton, AE, Majounie, E, Waite, A, Simón-Sánchez, J, Rollinson, S, Gibbs, JR, Schymick, JC, Laaksovirta, H, van Swieten, JC, Myllykangas, L, Kalimo, H, Paetau, A, Abramzon, Y, Remes, AM, Kaganovich, A, Scholz, SW, Duckworth, J, Ding, J, Harmer, DW, Hernandez, DG, Johnson, JO, Mok, K, Ryten, M, Trabzuni, D, Guerreiro, RJ, Orrell, RW, Neal, J, Murray, A, Pearson, J, Jansen, IE, Sondervan, D, Seelaar, H, Blake, D, Young, K, Halliwell, N, Callister, JB, Toulson, G, Richardson, A, Gerhard, A, Snowden, J, Mann, D, Neary, D, Nalls, MA, Peuralinna, T, Jansson, L, Isoviita, VM, Kaivorinne, AL, Hölttä-Vuori, M, Ikonen, E, Sulkava, R, Benatar, MG, Wuu, J, Chiò, A, Restagno, G, Borghero, G, Sabatelli, M, Heckerman, D, Rogaeva, E, Zinman, L, Rothstein, JD, Sendtner, M, Drepper, C, Eichler, EE, Alkan, C, Abdullaev, Z, Pack, SD, Dutra, A, Pak, E, Hardy, J, Singleton, A, Williams, NM, Heutink, P, Pickering-Brown, S, Morris, HR, Tienari, PJ & Traynor, BJ 2011, 'A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD', Neuron, vol. 72, no. 2, pp. 257-268. https://doi.org/10.1016/j.neuron.2011.09.010
Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011 Oct 20;72(2):257-268. https://doi.org/10.1016/j.neuron.2011.09.010
Renton, Alan E. ; Majounie, Elisa ; Waite, Adrian ; Simón-Sánchez, Javier ; Rollinson, Sara ; Gibbs, J. Raphael ; Schymick, Jennifer C. ; Laaksovirta, Hannu ; van Swieten, John C. ; Myllykangas, Liisa ; Kalimo, Hannu ; Paetau, Anders ; Abramzon, Yevgeniya ; Remes, Anne M. ; Kaganovich, Alice ; Scholz, Sonja W. ; Duckworth, Jamie ; Ding, Jinhui ; Harmer, Daniel W. ; Hernandez, Dena G. ; Johnson, Janel O. ; Mok, Kin ; Ryten, Mina ; Trabzuni, Danyah ; Guerreiro, Rita J. ; Orrell, Richard W. ; Neal, James ; Murray, Alex ; Pearson, Justin ; Jansen, Iris E. ; Sondervan, David ; Seelaar, Harro ; Blake, Derek ; Young, Kate ; Halliwell, Nicola ; Callister, Janis Bennion ; Toulson, Greg ; Richardson, Anna ; Gerhard, Alex ; Snowden, Julie ; Mann, David ; Neary, David ; Nalls, Michael A. ; Peuralinna, Terhi ; Jansson, Lilja ; Isoviita, Veli Matti ; Kaivorinne, Anna Lotta ; Hölttä-Vuori, Maarit ; Ikonen, Elina ; Sulkava, Raimo ; Benatar, Michael G ; Wuu, Joanne ; Chiò, Adriano ; Restagno, Gabriella ; Borghero, Giuseppe ; Sabatelli, Mario ; Heckerman, David ; Rogaeva, Ekaterina ; Zinman, Lorne ; Rothstein, Jeffrey D. ; Sendtner, Michael ; Drepper, Carsten ; Eichler, Evan E. ; Alkan, Can ; Abdullaev, Ziedulla ; Pack, Svetlana D. ; Dutra, Amalia ; Pak, Evgenia ; Hardy, John ; Singleton, Andrew ; Williams, Nigel M. ; Heutink, Peter ; Pickering-Brown, Stuart ; Morris, Huw R. ; Tienari, Pentti J. ; Traynor, Bryan J. / A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. In: Neuron. 2011 ; Vol. 72, No. 2. pp. 257-268.
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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.",
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