A Pan-European Study of the C9orf72 Repeat Associated with FTLD: Geographic Prevalence, Genomic Instability, and Intermediate Repeats

• Type: Article in International Scientific Journal
• Date: 2013

Authors

van der Zee, J (Author) Other; Gijselinck, I (Author) Other; Dillen, L (Author) Other; Van Langenhove, T (Author) Other; Theuns, J (Author) Other; Engelborghs, S (Author) Other; Philtjens, S (Author) Other; Vandenbulcke, M (Author) Other; Sleegers, K (Author) Other; Sieben, A (Author) Other; Bäumer, V (Author) Other; Maes, G (Author) Other; Corsmit, E (Author) Other; Borroni, B (Author) Other; Padovani, A (Author) Other; Archetti, S (Author) Other; Perneczky, R (Author) Other; Diehl-Schmid, J (Author) Other; de Mendonça, A (Author) Other; Miltenberger-Miltenyi, G (Author) Other; Pereira, S (Author) Other; Pimentel, J (Author) Other; Nacmias, B (Author) Other; Bagnoli, S (Author) Other; Sorbi, S (Author) Other; Graff, C (Author) Other; Chiang, H (Author) Other; Westerlund, M (Author) Other; Sanchez-Valle, R (Author) Other; Llado, A (Author) Other; Gelpi, E (Author) Other; Santana, I (Author) Other; Almeida, MR (Author) Other; Santiago, B (Author) Other; Frisoni, G (Author) Other; Zanetti, O (Author) Other; Bonvicini, C (Author) Other; Synofzik, M (Author) Other; Maetzler, W (Author) Other; vom Hagen, JM (Author) Other; Schöls, L (Author) Other; Heneka, MT (Author) Other; Jessen, F (Author) Other; Matej, R (Author) Other; Parobkova, E (Author) Other; Kovacs, GG (Author) Other; Ströbel, T (Author) Other; Sarafov, S (Author) Other; Tournev, I (Author) Other; Jordanova, A (Author) Other; Danek, A (Author) Other; Arzberger, T (Author) Other; Fabrizi, GM (Author) Other; Testi, S (Author) Other; Salmon, E (Author) Other; Santens, P (Author) Other; Martin, J (Author) Other; Cras, P (Author) Other; Vandenberghe, R (Author) Other; De Deyn, PP (Author) Other; Cruts, M (Author) Other; Van Broeckhoven, C (Author) Other; van der Zee, J (Author) Other; Gijselinck, I (Author) Other; Dillen, L (Author) Other; Van Langenhove, T (Author) Other; Theuns, J (Author) Other; Philtjens, S (Author) Other; Sleegers, K (Author) Other; Bäumer, V (Author) Other; Maes, G (Author) Other; Corsmit, E (Author) Other; Cruts, M (Author) Other; Van Broeckhoven, C (Author) Other; van der Zee, J (Author) Other; Gijselinck, I (Author) Other; Dillen, L (Author) Other; Van Langenhove, T (Author) Other; Philtjens, S (Author) Other; Theuns, J (Author) Other; Sleegers, K (Author) Other; Bäumer, V (Author) Other; Maes, G (Author) Other; Cruts, M (Author) Other; Van Broeckhoven, C (Author) Other; Engelborghs, S (Author) Other; De Deyn, PP (Author) Other; Cras, P (Author) Other; Engelborghs, S (Author) Other; De Deyn, PP (Author) Other; Vandenbulcke, M (Author) Other; Vandenbulcke, M (Author) Other; Borroni, B (Author) Other; Padovani, A (Author) Other; Archetti, S (Author) Other; Perneczky, R (Author) Other; Diehl-Schmid, J (Author) Other; Synofzik, M (Author) Other; Maetzler, W (Author) Other; Müller vom Hagen, J (Author) Other; Schöls, L (Author) Other; Synofzik, M (Author) Other; Maetzler, W (Author) Other; Müller vom Hagen, J (Author) Other; Schöls, L (Author) Other; Heneka, MT (Author) Other; Jessen, F (Author) Other; Ramirez, A (Author) Other; Kurzwelly, D (Author) Other; Sachtleben, C (Author) Other; Mairer, W (Author) Other; de Mendonça, A (Author) Other; Miltenberger-Miltenyi, G (Author) Other; Pereira, S (Author) Other; Firmo, C (Author) Other; Pimentel, J (Author) Other; Sanchez-Valle, R (Author) Other; Llado, A (Author) Other; Antonell, A (Author) Other; Molinuevo, J (Author) Other; Gelpi, E (Author) Other; Graff, C (Author) Other; Chiang, H (Author) Other; Westerlund, M (Author) Other; Graff, C (Author) Other; Kinhult Ståhlbom, A (Author) Other; Thonberg, H (Author) Other; Nennesmo, I (Author) Other; Börjesson-Hanson, A (Author) Other; Nacmias, B (Author) Other; Bagnoli, S (Author) Other; Sorbi, S (Author) Other; Bessi, V (Author) Other; Piaceri, I (Author) Other; Santana, I (Author) Other; Santiago, B (Author) Other; Santana, I (Author) Other; Helena Ribeiro, M (Author) Other; Rosário Almeida, M (Author) Other; Oliveira, C (Author) Other; João Massano (Author) FMUP; Garret, C (Author) Other; Pires, P (Author) Other; Frisoni, G (Author) Other; Zanetti, O (Author) Other; Bonvicini, C (Author) Other; Sarafov, S (Author) Other; Tournev, I (Author) Other; Jordanova, A (Author) Other; Tournev, I (Author) Other; Kovacs, GG (Author) Other; Ströbel, T (Author) Other; Heneka, MT (Author) Other; Jessen, F (Author) Other; Ramirez, A (Author) Other; Kurzwelly, D (Author) Other; Sachtleben, C (Author) Other; Mairer, W (Author) Other; Jessen, F (Author) Other; Matej, R (Author) Other; Parobkova, E (Author) Other; Danel, A (Author) Other; Arzberger, T (Author) Other; Maria Fabrizi, G (Author) Other; Testi, S (Author) Other; Ferrari, S (Author) Other; Cavallaro, T (Author) Other; Salmon, E (Author) Other; Santens, P (Author) Other; Cras, P (Author) Other

Journal

Title: Human Mutation

Vol. 34

Pages: 363-373

ISSN: 1059-7794

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 205 Citations

Scopus - 213 Citations

Other information

Authenticus ID: P-002-0T3

DOI: 10.1002/humu.22244

Abstract (EN): We assessed the geographical distribution of C9orf72 G4C2 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 (724 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 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

Type (Professor's evaluation): Scientific

No. of pages: 11