Publication
Title
A Pan-European study of the **C9orf72** repeat associated with FTLD : geographic prevalence, genomic instability and intermediate repeats
Author
Institution/Organisation
European Early-Onset Dementia (EOD) Consortium
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.
Language
English
Source (journal)
Human mutation. - New York, N.Y.
Publication
New York, N.Y. : 2013
ISSN
1059-7794
DOI
10.1002/HUMU.22244
Volume/pages
34 :2 (2013) , p. 363-373
ISI
000314477700014
Full text (Publisher's DOI)
Full text (open access)
UAntwerpen
Faculty/Department
Research group
Project info
An integrated approach to the unraveling of the pathogenesis of CNS and PNS neurodegenerative disorders.
Unraveling the genetic basis of epilepsies - a population based approach.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identifier
Creation 19.11.2012
Last edited 09.10.2023
To cite this reference