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A Pan‐ E uropean Study of the C9orf72 Repeat Associated with FTLD : Geographic Prevalence, Genomic Instability, and Intermediate Repeats

2012; Wiley; Volume: 34; Issue: 2 Linguagem: Inglês

10.1002/humu.22244

1098-1004

Julie van der Zee, Ilse Gijselinck, Lubina Dillen, Tim Van Langenhove, Jessie Theuns, Sebastiaan Engelborghs, Stéphanie Philtjens, Mathieu Vandenbulcke, Kristel Sleegers, Anne Sieben, Veerle Bäumer, Githa Maes, Ellen Corsmit, Barbara Borroni, Alessandro Padovani, Silvana Archetti, Robert Perneczky, Janine Diehl‐Schmid, Alexandre de Mendonça, Gábriel Miltenberger-Miltényi, Sónia Pereira, José Pimentel, Benedetta Nacmias, Silvia Bagnoli, Sandro Sorbi, Caroline Graff, Huei‐Hsin Chiang, Marie Westerlund, Raquel Sánchez‐Valle, Albert Lladó, Ellen Gelpí, Isabel Santana, Maria Rosário Almeida, Beatriz Santiago, Giovanni B. Frisoni, Orazio Zanetti, Cristian Bonvicini, Matthis Synofzik, Walter Maetzler, Jennifer Müller vom Hagen, Lüdger Schöls, Michael T. Heneka, Frank Jessen, Radoslav Matěj, Eva Parobková, Gábor G. Kovács, Thomas Ströbel, Stayko Sarafov, Ivailo Tournev, Albena Jordanova, Adrian Danek, Thomas Arzberger, Gian Maria Fabrizi, Silvia Testi, Éric Salmon, Patrick Santens, Jean‐Jacques Martin, Patrick Cras, Rik Vandenberghe, Peter Paul De Deyn, Marc Cruts, Christine Van Broeckhoven, Julie van der Zee, Ilse Gijselinck, Lubina Dillen, Tim Van Langenhove, Jessie Theuns, Stéphanie Philtjens, Kristel Sleegers, Veerle Bäumer, Githa Maes, Ellen Corsmit, Marc Cruts, Christine Van Broeckhoven, Julie van der Zee, Ilse Gijselinck, Lubina Dillen, Tim Van Langenhove, Stéphanie Philtjens, Jessie Theuns, Kristel Sleegers, Veerle Bäumer, Githa Maes, Marc Cruts, Christine Van Broeckhoven, Sebastiaan Engelborghs, Peter P. De Deyn, Patrick Cras, Sebastiaan Engelborghs, Peter P. De Deyn, Mathieu Vandenbulcke, Mathieu Vandenbulcke, Barbara Borroni, Alessandro Padovani, Silvana Archetti, Robert Perneczky, Janine Diehl‐Schmid, Matthis Synofzik, Walter Maetzler, Jennifer Müller vom Hagen, Lüdger Schöls, Matthis Synofzik, Walter Maetzler, Jennifer Müller vom Hagen, Lüdger Schöls, Michael T. Heneka, Frank Jessen, Alfredo Ramı́rez, Delia Kurzwelly, Carmen Sachtleben, Wolfgang Mairer, Alexandre de Mendonça, Gábriel Miltenberger-Miltényi, Sónia Pereira, Clara Firmo, José Pimentel, Raquel Sánchez‐Valle, Albert Lladó, Anna Antonell, José Luís Molinuevo, Ellen Gelpí, Caroline Graff, Huei‐Hsin Chiang, Marie Westerlund, Caroline Graff, Anne Kinhult Ståhlbom, Håkan Thonberg, Inger Nennesmo, Anne Börjesson‐Hanson, Benedetta Nacmias, Silvia Bagnoli, Sandro Sorbi, Valentina Bessi, Irene Piaceri, Isabel Santana, Beatriz Santiago, Isabel Santana, Maria Helena Ribeiro, Maria Rosário Almeida, Catarina R. Oliveira, João Massano, Carolina Garret, Paula Pires, Giovanni B. Frisoni, Orazio Zanetti, Cristian Bonvicini, Stayko Sarafov, Ivailo Tournev, Albena Jordanova, Ivailo Tournev, Gábor G. Kovács, Thomas Ströbel, Michael T. Heneka, Frank Jessen, Alfredo Ramı́rez, Delia Kurzwelly, Carmen Sachtleben, Wolfgang Mairer, Frank Jessen, Radoslav Matěj, Eva Parobková, Adrian Danel, Thomas Arzberger, Gian Maria Fabrizi, Silvia Testi, Sérgio Ferrari, Tiziana Cavallaro, Éric Salmon, Patrick Santens, Patrick Cras,

Connective tissue disorders research

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 (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 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.