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

被引：3337

作者：

Renton, Alan E. ^{[1
]}

Majounie, Elisa ^{[2
]}

Waite, Adrian ^{[3
]}

Simon-Sanchez, Javier ^{[4
,5
,6
]}

Rollinson, Sara ^{[7
]}

Gibbs, J. Raphael ^{[8
,9
]}

Schymick, Jennifer C. ^{[1
]}

Laaksovirta, Hannu ^{[10
,11
]}

van Swieten, John C. ^{[4
,5
,6
]}

Myllykangas, Liisa ^{[12
,13
]}

Kalimo, Hannu ^{[12
,13
]}

Paetau, Anders ^{[12
,13
]}

Abramzon, Yevgeniya ^{[1
]}

Remes, Anne M. ^{[14
,15
]}

Kaganovich, Alice ^{[16
]}

Scholz, Sonja W. ^{[2
,17
,18
]}

Duckworth, Jamie

Ding, Jinhui

Harmer, Daniel W. ^{[19
]}

Hernandez, Dena G. ^{[2
,8
,9
]}

Johnson, Janel O. ^{[1
,8
,9
]}

Mok, Kin ^{[8
,9
]}

Ryten, Mina ^{[8
,9
]}

Trabzuni, Danyah ^{[8
,9
]}

Guerreiro, Rita J. ^{[8
,9
]}

Orrell, Richard W. ^{[20
]}

Neal, James ^{[21
]}

Murray, Alex ^{[22
]}

Pearson, Justin ^{[3
]}

Jansen, Iris E. ^{[4
,5
]}

Sondervan, David ^{[4
,5
]}

Seelaar, Harro ^{[6
]}

Blake, Derek ^{[3
]}

Young, Kate ^{[7
]}

Halliwell, Nicola ^{[7
]}

Callister, Janis Bennion ^{[7
]}

Toulson, Greg ^{[7
]}

Richardson, Anna ^{[23
]}

Gerhard, Alex ^{[23
]}

Snowden, Julie ^{[23
]}

Mann, David ^{[23
]}

Neary, David ^{[23
]}

Nalls, Michael A. ^{[2
]}

Peuralinna, Terhi ^{[10
,11
]}

Jansson, Lilja ^{[10
,11
]}

Isoviita, Veli-Matti ^{[10
,11
]}

Kaivorinne, Anna-Lotta ^{[14
,15
]}

Holtta-Vuori, Maarit ^{[24
]}

Ikonen, Elina ^{[24
]}

Sulkava, Raimo ^{[25
]}

机构：

[1] NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[2] NIA, Mol Genet Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[3] Cardiff Univ, Sch Med, MRC Ctr Neuropsychiatr Genet & Genom, Cardiff CF14 4XN, Wales

[4] Vrije Univ Amsterdam, Med Ctr, Depat Clin Genet, Sect Med Genom, NL-1081 HV Amsterdam, Netherlands

[5] Vrije Univ Amsterdam, Med Ctr, Alzheimer Dis Ctr, NL-1081 HV Amsterdam, Netherlands

[6] Erasmus MC Univ Med Ctr Rotterdam, Dept Neurol, NL-3015 CE Rotterdam, Netherlands

[7] Univ Manchester, Fac Human & Med Sci, Manchester M13 9PT, Lancs, England

[8] UCL, Dept Mol Neurosci, London WC1N 3BG, England

[9] UCL, Reta Lila Weston Labs, Inst Neurol, London WC1N 3BG, England

[10] Univ Helsinki, Dept Neurol, Cent Hosp, FIN-02900 Helsinki, Finland

[11] Univ Helsinki, Mol Neurol Programme, Biomedicum, FIN-02900 Helsinki, Finland

[12] Univ Helsinki, Dept Pathol, Haartman Inst HUSLAB, FIN-02900 Helsinki, Finland

[13] Folkhalsan Res Ctr LM, FIN-02900 Helsinki, Finland

[14] Univ Oulu, Inst Clin Med, FIN-90014 Oulu, Finland

[15] Oulu Univ Hosp, Clin Res Ctr, FIN-90014 Oulu, Finland

[16] NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[17] Georgetown Univ, Dept Neurosci, Washington, DC 20057 USA

[18] Johns Hopkins Univ, Dept Neurol, Brain Sci Inst, Baltimore, MD 21287 USA

[19] Illumina Inc, Hayward, CA 94545 USA

[20] UCL, Dept Clin Neurosci, Inst Neurol, London NW3 2PG, England

[21] Cardiff Univ, Sch Med, Dept Pathol, Cardiff CF14 4XN, S Glam, Wales

[22] Univ Wales Hosp, Inst Med Genet, Cardiff CF14 4XW, S Glam, Wales

[23] Univ Manchester, Neurodegenerat & Mental Hlth Res Grp, Cerebral Funct Unit, Sch Community Based Med, Manchester M6 8HD, Lancs, England

[24] Univ Helsinki, Inst Biomed Anat, FIN-00014 Helsinki, Finland

[25] Univ Eastern Finland, Sect Geriatr, Inst Publ Hlth & Clin Nutr, FIN-70211 Kuopio, Finland

[26] Univ Miami, Miller Sch Med, Neuromuscular Div, Dept Neurol, Miami, FL 33136 USA

[27] Univ Miami, Miller Sch Med, Clin Translat Res Div, Dept Neurol, Miami, FL 33136 USA

[28] Univ Turin, Dept Neurosci, I-10126 Turin, Italy

[29] ASOOIRM S Anna, Mol Genet Unit, Dept Clin Pathol, I-10126 Turin, Italy

[30] Azienda Univ Osped Cagliari, Dept Neurol, I-09042 Cagliari, Italy

[31] Univ Cagliari, I-09042 Cagliari, Italy

[32] Catholic Univ, Neurol Inst, I-10100 Rome, Italy

[33] ICOMM Assoc ALS Res, I-10100 Rome, Italy

[34] Microsoft Res, Los Angeles, CA 90024 USA

[35] Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON M5S 3H2, Canada

[36] Univ Toronto, Toronto Western Hosp, Div Neurol, Dept Med, Toronto, ON M5S 3H2, Canada

[37] Univ Toronto, Div Neurol, Dept Internal Med, Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada

[38] Univ Wurzburg, Inst Clin Neurobiol, D-97078 Wurzburg, Germany

[39] Univ Washington, Sch Med, Howard Hughes Med Inst, Seattle, WA 98195 USA

[40] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA

[41] NCI, Chromosome Pathol Unit, Pathol Lab, NIH, Bethesda, MD 20892 USA

[42] NHGRI, NIH, Bethesda, MD 20892 USA

[43] Aneurin Bevan Local Hlth Board, Dept Neurol, Royal Gwent Hosp, Newport NP20 2UB, Gwent, Wales

来源：

NEURON | 2011年 / 72卷 / 02期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; HUMAN GENOME; MUTATIONS; TDP-43; DEMENTIA; SUSCEPTIBILITY; ASSOCIATION; POPULATION; COMMON;

D O I：

10.1016/j.neuron.2011.09.010

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：257 / 268

页数：12

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