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; 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

doi:10.1016/j.neuron.2011.09.010

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 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

The University of Manchester

Research output: Contribution to journal › Article › peer-review

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. © 2011 Elsevier Inc.

Original language	English
Pages (from-to)	257-268
Number of pages	11
Journal	Neuron
Volume	72
Issue number	2
DOIs	https://doi.org/10.1016/j.neuron.2011.09.010
Publication status	Published - 20 Oct 2011

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10.1016/j.neuron.2011.09.010

The global impact of gene identification at the University of Manchester
Read, A. (Participant), Tassabehji, M. (Participant), Dixon, M. (Participant), Black, G. (Participant), Clayton-Smith, J. (Participant), Newman, W. (Participant), Crow, Y. (Participant), Thakkar, N. (Participant), Briggs, M. (Participant) & Pickering-Brown, S. (Participant)
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Renton, A. E., Majounie, E., Waite, A., Simón-Sánchez, J., Rollinson, S., Gibbs, J. R., Schymick, J. C., Laaksovirta, H., van Swieten, J. C., Myllykangas, L., Kalimo, H., Paetau, A., Abramzon, Y., Remes, A. M., Kaganovich, A., Scholz, S. W., Duckworth, J., Ding, J., Harmer, D. W., ... 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

@article{bdf0db430f1540f3afb17f1c0b251ee4,

title = "A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD",

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. {\textcopyright} 2011 Elsevier Inc.",

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

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doi = "10.1016/j.neuron.2011.09.010",

language = "English",

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pages = "257--268",

journal = "Neuron",

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publisher = "Cell Press",

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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, M, 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

TY - JOUR

T1 - A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD

AU - Renton, Alan E.

AU - Majounie, Elisa

AU - Waite, Adrian

AU - Simón-Sánchez, Javier

AU - Rollinson, Sara

AU - Gibbs, J. Raphael

AU - Schymick, Jennifer C.

AU - Laaksovirta, Hannu

AU - van Swieten, John C.

AU - Myllykangas, Liisa

AU - Kalimo, Hannu

AU - Paetau, Anders

AU - Abramzon, Yevgeniya

AU - Remes, Anne M.

AU - Kaganovich, Alice

AU - Scholz, Sonja W.

AU - Duckworth, Jamie

AU - Ding, Jinhui

AU - Harmer, Daniel W.

AU - Hernandez, Dena G.

AU - Johnson, Janel O.

AU - Mok, Kin

AU - Ryten, Mina

AU - Trabzuni, Danyah

AU - Guerreiro, Rita J.

AU - Orrell, Richard W.

AU - Neal, James

AU - Murray, Alex

AU - Pearson, Justin

AU - Jansen, Iris E.

AU - Sondervan, David

AU - Seelaar, Harro

AU - Blake, Derek

AU - Young, Kate

AU - Halliwell, Nicola

AU - Callister, Janis Bennion

AU - Toulson, Greg

AU - Richardson, Anna

AU - Gerhard, Alex

AU - Snowden, Julie

AU - Mann, David

AU - Neary, David

AU - Nalls, Michael A.

AU - Peuralinna, Terhi

AU - Jansson, Lilja

AU - Isoviita, Veli Matti

AU - Kaivorinne, Anna Lotta

AU - Hölttä-Vuori, Maarit

AU - Ikonen, Elina

AU - Sulkava, Raimo

AU - Benatar, Michael

AU - Wuu, Joanne

AU - Chiò, Adriano

AU - Restagno, Gabriella

AU - Borghero, Giuseppe

AU - Sabatelli, Mario

AU - Heckerman, David

AU - Rogaeva, Ekaterina

AU - Zinman, Lorne

AU - Rothstein, Jeffrey D.

AU - Sendtner, Michael

AU - Drepper, Carsten

AU - Eichler, Evan E.

AU - Alkan, Can

AU - Abdullaev, Ziedulla

AU - Pack, Svetlana D.

AU - Dutra, Amalia

AU - Pak, Evgenia

AU - Hardy, John

AU - Singleton, Andrew

AU - Williams, Nigel M.

AU - Heutink, Peter

AU - Pickering-Brown, Stuart

AU - Morris, Huw R.

AU - Tienari, Pentti J.

AU - Traynor, Bryan J.

PY - 2011/10/20

Y1 - 2011/10/20

N2 - 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. © 2011 Elsevier Inc.

AB - 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. © 2011 Elsevier Inc.

U2 - 10.1016/j.neuron.2011.09.010

DO - 10.1016/j.neuron.2011.09.010

M3 - Article

C2 - 21944779

SN - 0896-6273

VL - 72

SP - 257

EP - 268

JO - Neuron

JF - Neuron

IS - 2

ER -

A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD

Abstract

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The global impact of gene identification at the University of Manchester

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