A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD

A.E. Renton; E. Majounie; A. Waite; J. Simon-Sanchez; S. Rollinson; J.R. Gibbs; J.C. Schymick; H. Laaksovirta; J.C. van Swieten; L. Myllykangas; H. Kalimo; A. Paetau; Y. Abramzon; A.M. Remes; A. Kaganovich; S.W. Scholz; J. Duckworth; J.H. Ding; D.W. Harmer; D.G. Hernandez; J.O. Johnson; K. Mok; M. Ryten; D. Trabzuni; R.J. Guerreiro; R.W. Orrell; J. Neal; A. Murray; J. Pearson; I.E. Jansen; D. Sondervan; H. Seelaar; D. Blake; K. Young; N. Halliwell; J.B. Callister; G. Toulson; A. Richardson; A. Gerhard; J. Snowden; D. Mann; D. Neary; M.A. Nalls; T. Peuralinna; L. Jansson; V.M. Isoviita; A.L. Kaivorinne; M. Holtta-Vuori; E. Ikonen; R. Sulkava; M. Benatar; J. Wuu; A. Chio; G. Restagno; G. Borghero; M. Sabatelli; D. Heckerman; E. Rogaeva; L. Zinman; J.D. Rothstein; M. Sendtner; C. Drepper; E.E. Eichler; C. Alkan; Z. Abdullaev; S.D. Pack; A. Dutra; E. Pak; J. Hardy; A. Singleton; N. M. Williams; P. Heutink; S. Pickering-Brown; H.R. Morris; P.J. Tienari; B.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

A.E. Renton, E. Majounie, A. Waite, J. Simon-Sanchez, S. Rollinson, J.R. Gibbs, J.C. Schymick, H. Laaksovirta, J.C. van Swieten, L. Myllykangas, H. Kalimo, A. Paetau, Y. Abramzon, A.M. Remes, A. Kaganovich, S.W. Scholz, J. Duckworth, J.H. Ding, D.W. Harmer, D.G. HernandezJ.O. Johnson, K. Mok, M. Ryten, D. Trabzuni, R.J. Guerreiro, R.W. Orrell, J. Neal, A. Murray, J. Pearson, I.E. Jansen, D. Sondervan, H. Seelaar, D. Blake, K. Young, N. Halliwell, J.B. Callister, G. Toulson, A. Richardson, A. Gerhard, J. Snowden, D. Mann, D. Neary, M.A. Nalls, T. Peuralinna, L. Jansson, V.M. Isoviita, A.L. Kaivorinne, M. Holtta-Vuori, E. Ikonen, R. Sulkava, M. Benatar, J. Wuu, A. Chio, G. Restagno, G. Borghero, M. Sabatelli, D. Heckerman, E. Rogaeva, L. Zinman, J.D. Rothstein, M. Sendtner, C. Drepper, E.E. Eichler, C. Alkan, Z. Abdullaev, S.D. Pack, A. Dutra, E. Pak, J. Hardy, A. Singleton, N. M. Williams, P. Heutink, S. Pickering-Brown, H.R. Morris, P.J. Tienari, B.J. Traynor

Research output: Contribution to Journal › Article › Academic › 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
Journal	Neuron
Volume	72
Issue number	2
DOIs	https://doi.org/10.1016/j.neuron.2011.09.010
Publication status	Published - 2011

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Renton, A. E., Majounie, E., Waite, A., Simon-Sanchez, 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. H., 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{43ac11670bfb43c8a24650dcf9310208,

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 = "A.E. Renton and E. Majounie and A. Waite and J. Simon-Sanchez and S. Rollinson and J.R. Gibbs and J.C. Schymick and H. Laaksovirta and \{van Swieten\}, J.C. and L. Myllykangas and H. Kalimo and A. Paetau and Y. Abramzon and A.M. Remes and A. Kaganovich and S.W. Scholz and J. Duckworth and J.H. Ding and D.W. Harmer and D.G. Hernandez and J.O. Johnson and K. Mok and M. Ryten and D. Trabzuni and R.J. Guerreiro and R.W. Orrell and J. Neal and A. Murray and J. Pearson and I.E. Jansen and D. Sondervan and H. Seelaar and D. Blake and K. Young and N. Halliwell and J.B. Callister and G. Toulson and A. Richardson and A. Gerhard and J. Snowden and D. Mann and D. Neary and M.A. Nalls and T. Peuralinna and L. Jansson and V.M. Isoviita and A.L. Kaivorinne and M. Holtta-Vuori and E. Ikonen and R. Sulkava and M. Benatar and J. Wuu and A. Chio and G. Restagno and G. Borghero and M. Sabatelli and D. Heckerman and E. Rogaeva and L. Zinman and J.D. Rothstein and M. Sendtner and C. Drepper and E.E. Eichler and C. Alkan and Z. Abdullaev and S.D. Pack and A. Dutra and E. Pak and J. Hardy and A. Singleton and Williams, \{N. M.\} and P. Heutink and S. Pickering-Brown and H.R. Morris and P.J. Tienari and B.J. Traynor",

year = "2011",

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

language = "English",

volume = "72",

pages = "257--268",

journal = "Neuron",

issn = "0896-6273",

publisher = "Cell Press",

number = "2",

}

Renton, AE, Majounie, E, Waite, A, Simon-Sanchez, 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, JH, 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, Holtta-Vuori, M, Ikonen, E, Sulkava, R, Benatar, M, Wuu, J, Chio, 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, A.E.

AU - Majounie, E.

AU - Waite, A.

AU - Simon-Sanchez, J.

AU - Rollinson, S.

AU - Gibbs, J.R.

AU - Schymick, J.C.

AU - Laaksovirta, H.

AU - van Swieten, J.C.

AU - Myllykangas, L.

AU - Kalimo, H.

AU - Paetau, A.

AU - Abramzon, Y.

AU - Remes, A.M.

AU - Kaganovich, A.

AU - Scholz, S.W.

AU - Duckworth, J.

AU - Ding, J.H.

AU - Harmer, D.W.

AU - Hernandez, D.G.

AU - Johnson, J.O.

AU - Mok, K.

AU - Ryten, M.

AU - Trabzuni, D.

AU - Guerreiro, R.J.

AU - Orrell, R.W.

AU - Neal, J.

AU - Murray, A.

AU - Pearson, J.

AU - Jansen, I.E.

AU - Sondervan, D.

AU - Seelaar, H.

AU - Blake, D.

AU - Young, K.

AU - Halliwell, N.

AU - Callister, J.B.

AU - Toulson, G.

AU - Richardson, A.

AU - Gerhard, A.

AU - Snowden, J.

AU - Mann, D.

AU - Neary, D.

AU - Nalls, M.A.

AU - Peuralinna, T.

AU - Jansson, L.

AU - Isoviita, V.M.

AU - Kaivorinne, A.L.

AU - Holtta-Vuori, M.

AU - Ikonen, E.

AU - Sulkava, R.

AU - Benatar, M.

AU - Wuu, J.

AU - Chio, A.

AU - Restagno, G.

AU - Borghero, G.

AU - Sabatelli, M.

AU - Heckerman, D.

AU - Rogaeva, E.

AU - Zinman, L.

AU - Rothstein, J.D.

AU - Sendtner, M.

AU - Drepper, C.

AU - Eichler, E.E.

AU - Alkan, C.

AU - Abdullaev, Z.

AU - Pack, S.D.

AU - Dutra, A.

AU - Pak, E.

AU - Hardy, J.

AU - Singleton, A.

AU - Williams, N. M.

AU - Heutink, P.

AU - Pickering-Brown, S.

AU - Morris, H.R.

AU - Tienari, P.J.

AU - Traynor, B.J.

PY - 2011

Y1 - 2011

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.

UR - https://www.scopus.com/pages/publications/80054837386

UR - https://www.scopus.com/inward/citedby.url?scp=80054837386&partnerID=8YFLogxK

U2 - 10.1016/j.neuron.2011.09.010

DO - 10.1016/j.neuron.2011.09.010

M3 - Article

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

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