The C9orf72 hexanucleotide repeat expansion in FTD and ALS

Department of Pathology and Northwestern University Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, 710 North Fairbanks Court, Olson 2-458, Chicago, IL 60611, USA. .
Nature Reviews Neurology (Impact Factor: 15.36). 04/2012; 8(5):249-50. DOI: 10.1038/nrneurol.2012.58
Source: PubMed


Two new studies provide strong evidence for the link between mutations in the C9orf72 gene and familial frontotemporal dementia or amyotrophic lateral sclerosis. One of the papers presents some unique associations between clinical features and C9orf72 mutation, and raises questions regarding the specificity of some previously reported pathological findings.

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    • "repeat expansion mutation establishing C9orf72 as a major gene for FTLD with frequencies of 7%–11% in total FTLD and 12%–25% in familial FTLD patients [Boeve et al., 2012; DeJesus-Hernandez et al., 2011; Ferrari et al., 2012; Gijselinck et al., 2012; Hsiung et al., 2012; Mahoney et al., 2012; Majounie 2012; Renton et al., 2011; Simon-Sanchez et al., 2012; Snowden et al., 2012]. Different possible disease mechanisms have been proposed including haploinsufficiency and RNA toxicity [Dejesus-Hernandez et al., 2011; Gijselinck et al., 2012] and extensive genotype– phenotype correlation studies are being reported [Al-Sarraj et al., 2011; Arighi et al., 2012; Bigio, 2012; Boeve et al., 2012; Chio et al., 2012; Dejesus-Hernandez et al., 2011; Ferrari et al., 2012; Gijselinck et al., 2012; Hsiung et al., 2012; Majounie et al., 2012; Mahoney et al., 2012; Murray et al., 2011; Renton et al., 2011; Simon-Sanchez et al., 2012; Snowden et al., 2012; Troakes et al., 2011; Whitwell et al., 2012]. However, very little or nothing is known about the mutation spectrum, the genomic mechanism by which the G 4 C 2 repeat is expanding , and the impact of repeat length on disease susceptibility and gene expression. "
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    ABSTRACT: We assessed the geographical distribution of C9orf72 G(4) C(2) expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n = 1205), ascertained by the European Early-Onset Dementia (EOD) consortium. Next, we performed a meta-analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7 to 24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss-of-function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC-rich low complexity sequence (LCS) adjacent to the G(4) C(2) repeat in C9orf72 expansion carriers (p < 0.001) with the most common indel creating one long contiguous imperfect G(4) C(2) repeat which is likely more prone to replication slippage and pathological expansion.
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