Title
A Pan-European study of the **C9orf72** repeat associated with FTLD : geographic prevalence, genomic instability and intermediate repeats A Pan-European study of the **C9orf72** repeat associated with FTLD : geographic prevalence, genomic instability and intermediate repeats
Author
Faculty/Department
Faculty of Sciences. Biology
Faculty of Medicine and Health Sciences
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Publication type
article
Publication
New York, N.Y. ,
Subject
Biology
Human medicine
Source (journal)
Human mutation. - New York, N.Y.
Volume/pages
34(2013) :2 , p. 363-373
ISSN
1059-7794
ISI
000314477700014
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
We assessed the geographical distribution of C9orf72 G4C2 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 G4C2 repeat in C9orf72 expansion carriers (p < 0.001) with the most common indel creating one long contiguous imperfect G4C2 repeat which is likely more prone to replication slippage and pathological expansion.
Full text (open access)
https://repository.uantwerpen.be/docman/irua/3bef36/abc8d3ef.pdf
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