Verslag – Rapport – Bericht – Report - GSKE - FMRE

was reported in detail in the 2011 report. Here we report on an international follow-up study and on the
exploration of the effect of the repeat expansion on gene expression.
In 2006, we identified GRN null mutations as a major gene for FTLD explaining 26 % of familial FTLD in
Belgium (Cruts et al., 2006). Now, we published a paper describing the generation and detailed genetic,
clinical, behavioral and immunohistochemical characterization of GRN knock-out mize.
C9orf72
We assessed the geographical distribution of C9orf72 G 4 C 2 repeat expansions in a collection of 1,205
European FTLD patients, ascertained by the European Early-Onset Dementia (EOD) consortium. Next,
we performed a meta-analysis of these data and that of other European studies, together 2,668 patients
from 15 Western European countries. The frequency of C9orf72 repeat expansions in Western Europe
was 9.98%, 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% (van der Zee and Gijselinck et al., 2012).
Intermediate repeat sizes (7 to 24 repeat units) are strongly correlated with a haplotype conferring
significant risk especially for developing ALS and FTLD-TDP (van Es et al., 2009; Laaksovirta et al.,
2010; Shatunov et al., 2010; Van Deerlin et al., 2010). We studied the role of intermediate repeat sizes
on C9orf72 gene expression. In vitro reporter gene expression studies demonstrated significantly
decreased transcriptional activity of C9orf72 with increasing number of repeat units (Figure 1), 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 (van der Zee and Gijselinck et al., 2012).
Figure 1. Transcriptional acti vi ty of C9orf72 promoter with alleles of different repeat length. Bars represent relative Gaussia/
Cypridina luciferase ac ti vities (RLA) for the different C9orf72 constructs compared to the wild type allele of 2 units, for an increasing
amount of repeat units. Values represent the mean (±SDEV) of 36 independent measure ments relative to the 2 units wild type allele. The
significance of differences in expression was calculated using the Mann-Whitney U test. P-values are presented above the bars (van der
Zee and Gijselinck et al., 2012).
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Verslag – Rapport – Report 2012