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

Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Neuron (Impact Factor: 15.98). 09/2011; 72(2):257-68. DOI: 10.1016/j.neuron.2011.09.010
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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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    Frontiers in Molecular Neuroscience 03/2015; 8:9. DOI:10.3389/fnmol.2015.00009
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    • "Since the initial discoveries, many more diseases have been identified that are caused by repeat expansions, most of which are trinucleotide repeats, although several diseases are caused by repeats of larger units. Examples include SCA10 caused by an ATTCT expansion (Matsuura et al., 2000) and the recently identified G 4 C 2 repeat expansion in the c9orf72 gene, which is the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (DeJesus-Hernandez et al., 2011; Renton et al., 2011) (Table 1). In addition, it has recently been recognized that different sized expansions can in some cases result in different disease phenotypes. "
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    • "However, no genomic DNA was available from other family members to study the patterns of segregation and anticipation, and no other FALS cases possessed this expansion. Tandem repeats are frequently associated with neurodegenerative diseases, such as Huntington's disease and spinocerebellar ataxias and have recently been shown to be the most common mutation found in ALS, FTD and ALS/FTD, with the identification of hexanucleotide repeat expansions in the first intron of the C9orf72 gene, located on chromosome 9p21 accounting for 18–55% of FALS cases according to geographic location , being most prevalent in Western Europe [16] [17] [18]. Tri-nucleotide expansions in the NIPA1 [19] and ATXN2 [20] genes also confer risk of ALS. "
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