C9orf72 Protein; C9orf72 protein, human; Proteins; Adult; Age of Onset; Aged; Aged, 80 and over; Alleles; Alzheimer Disease/genetics; Base Sequence; Chromosomes, Human, Pair 9/genetics; Cohort Studies; DNA Repeat Expansion; Europe/epidemiology; Finland/epidemiology; Frontotemporal Lobar Degeneration/epidemiology; Frontotemporal Lobar Degeneration/genetics; Genome-Wide Association Study/methods; Germany/epidemiology; Haplotypes; Humans; Middle Aged; Molecular Sequence Data; Prevalence; Proteins/genetics; Spain/epidemiology; Sweden/epidemiology; Genomic Instability; C9orf72; European Early-Onset Dementia consortium; FTLD; Intermediate alleles; Repeat expansion; Genetics; Genetics (clinical)
Abstract :
[en] We assessed the geographical distribution of C9orf72 G(4) C(2) expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), 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 (7-24 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 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.
Disciplines :
Neurology
Author, co-author :
van der Zee, Julie ✱; Department of Molecular Genetics, VIB, Antwerp, Belgium
Gijselinck, Ilse ✱
Dillen, Lubina
Van Langenhove, Tim
Theuns, Jessie
Engelborghs, Sebastiaan
Philtjens, Stéphanie
Vandenbulcke, Mathieu
Sleegers, Kristel
Sieben, Anne
Bäumer, Veerle
Maes, Githa
Corsmit, Ellen
Borroni, Barbara
Padovani, Alessandro
Archetti, Silvana
Perneczky, Robert
Diehl-Schmid, Janine
de Mendonça, Alexandre
Miltenberger-Miltenyi, Gabriel
Pereira, Sónia
Pimentel, José
Nacmias, Benedetta
Bagnoli, Silvia
Sorbi, Sandro
Graff, Caroline
Chiang, Huei-Hsin
Westerlund, Marie
Sanchez-Valle, Raquel
Llado, Albert
Gelpi, Ellen
Santana, Isabel
Almeida, Maria Rosário
Santiago, Beatriz
Frisoni, Giovanni
Zanetti, Orazio
Bonvicini, Cristian
Synofzik, Matthis
Maetzler, Walter
Vom Hagen, Jennifer Müller
Schöls, Ludger
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