Dataset Information

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.

SUBMITTER: Renton AE

PROVIDER: S-EPMC3200438 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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

Renton Alan E AE Majounie Elisa E Waite Adrian A Simón-Sánchez Javier J Rollinson Sara S Gibbs J Raphael JR Schymick Jennifer C JC Laaksovirta Hannu H van Swieten John C JC Myllykangas Liisa L Kalimo Hannu H Paetau Anders A Abramzon Yevgeniya Y Remes Anne M AM Kaganovich Alice A Scholz Sonja W SW Duckworth Jamie J Ding Jinhui J Harmer Daniel W DW Hernandez Dena G DG Johnson Janel O JO Mok Kin K Ryten Mina M Trabzuni Danyah D Guerreiro Rita J RJ Orrell Richard W RW Neal James J Murray Alex A Pearson Justin J Jansen Iris E IE Sondervan David D Seelaar Harro H Blake Derek D Young Kate K Halliwell Nicola N Callister Janis Bennion JB Toulson Greg G Richardson Anna A Gerhard Alex A Snowden Julie J Mann David D Neary David D Nalls Michael A MA Peuralinna Terhi T Jansson Lilja L Isoviita Veli-Matti VM Kaivorinne Anna-Lotta AL Hölttä-Vuori Maarit M Ikonen Elina E Sulkava Raimo R Benatar Michael M Wuu Joanne J Chiò Adriano A Restagno Gabriella G Borghero Giuseppe G Sabatelli Mario M Heckerman David D Rogaeva Ekaterina E Zinman Lorne L Rothstein Jeffrey D JD Sendtner Michael M Drepper Carsten C Eichler Evan E EE Alkan Can C Abdullaev Ziedulla Z Pack Svetlana D SD Dutra Amalia A Pak Evgenia E Hardy John J Singleton Andrew A Williams Nigel M NM Heutink Peter P Pickering-Brown Stuart S Morris Huw R HR Tienari Pentti J PJ Traynor Bryan J BJ

Neuron 20110921 2

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 ...[more]

PMID: 21944779

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Project description:Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of a disease spectrum associated with TDP-43 pathology. Strong evidence supporting this is the existence of kindreds with family members affected by FTD, ALS or mixed features of FTD and ALS, referred to as FTD-MND. Some of these families have linkage to chromosome 9, with hexanucleotide expansion mutation in a noncoding region of C9ORF72. Discovery of the mutation defines c9FTD/ALS. Prior to discovery of mutations in C9ORF72, it was assumed that TDP-43 pathology in c9FTD/ALS was uniform. In this study, we examined the neuropathology and clinical features of 20 cases of c9FTD/ALS from a brain bank for neurodegenerative disorders. Included are six patients clinically diagnosed with ALS, eight FTD, one FTD-MND and four Alzheimer-type dementia. Clinical information was unavailable for one patient. Pathologically, the cases all had TDP-43 pathology, but there were three major pathologic groups: ALS, FTLD-MND and FTLD-TDP. The ALS cases were morphologically similar to typical sporadic ALS with almost no extramotor TDP-43 pathology; all had oligodendroglial cytoplasmic inclusions. The FTLD-MND showed predominantly Mackenzie Type 3 TDP-43 pathology, and all had ALS-like pathology in motor neurons, but more extensive extramotor pathology, with oligodendroglial cytoplasmic inclusions and infrequent hippocampal sclerosis. The FTLD-TDP cases had several features similar to FTLD-TDP due to mutations in the gene for progranulin, including Mackenzie Type 1 TDP-43 pathology with neuronal intranuclear inclusions and hippocampal sclerosis. FTLD-TDP patients were older and some were thought to have Alzheimer-type dementia. In addition to the FTD and ALS clinical presentations, the present study shows that c9FTD/ALS can have other presentations, possibly related to age of onset and the presence of hippocampal sclerosis. Moreover, there is pathologic heterogeneity not only between ALS and FTLD, but also within the FTLD group. Further studies are needed to address the molecular mechanism of clinical and pathological heterogeneity of c9FTD/ALS due to mutations in C9ORF72.

Dataset Information

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

Publications

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

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