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

By A. Renton, E. Majounie, A. Waite, J. Simón-Sánchez, S. Rollinson, J. R. Gibbs, Jennifer Schymick, Hannu Laaksovirta, J. Swieten, L. Myllykangas and 66 more. Neuron, 2011

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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.

Subfields: Genetics, Neurology

View Paper: https://www.semanticscholar.org/paper/c7c83cfbca107abf0121e84b7c6b5ee5dde076dc

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Citations in the corpus

Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities. (2017, positive): “The most common cause of ALS is a hexanucleotide repeat expansion in the C9ORF72 gene (DeJesus-Hernandez et al., 2011; Renton et al., 2011).”
The Next-Generation Sequencing Revolution and Its Impact on Genomics (2013, positive): “Nearly half of familial ALS in Finnish populations, for example, is caused by a hexanucleotide repeat expansion in the intron of the C9orf72 gene (Renton et al., 2011 ).”
Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. (2013, positive): “Two independent groups recently identified a hexanucleotide (GGGGCC) repeat expansion in a noncoding region of C9ORF72 as the most frequent genetic cause of ALS and FTD (c9FTD/ALS) (DeJesus-Hernandez et al., 2011; Renton et al., 2011), firmly establishing a genetic link between the two disorders.”
Pathology of Neurodegenerative Diseases. (2017, background): “Type B, which can be associated with motor neuron disease, is predominantly characterized by neuronal cytoplasmic inclusions with few or no neurites and no neuronal intranuclear inclusions, as occurs most commonly in patients with hexanucleotide expansions in the C9ORF72 gene (DeJesus-Hernandez et a”
Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023, background): “304,335 The mechanism by which these repeat expansions may cause disease is outlined in three hypotheses: ﬁ rst, downregulation of gene expression (haploinsuf ﬁ ciency) leads to a loss of C9orf72 ’ s normal cellular function; second, the presence of sense and antisense RNA foci could sequester…”
Frequency of the C9ORF72 hexanucleotide repeat expansion in ALS and FTD in diverse populations: a cross-sectional study (2012, positive): “Of the 2,585 neurologically normal control individuals from Australia (n = 213), Finland (n = 478), Germany (n = 309), Human Gene Diversity Panel (n = 300), Italian (n = 354), Sardinian (n = 87), and the United States (n = 844) that have been screened for the presence of the pathogenic repeat expans”