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A Pan‐ E uropean Study of the C9orf72 Repeat Associated with FTLD : Geographic Prevalence, Genomic Instability, and Intermediate Repeats
Author(s) -
van der Zee Julie,
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,
DiehlSchmid Janine,
de Mendonça Alexandre,
MiltenbergerMiltenyi Gabriel,
Pereira Sónia,
Pimentel José,
Nacmias Benedetta,
Bagnoli Silvia,
Sorbi Sandro,
Graff Caroline,
Chiang HueiHsin,
Westerlund Marie,
SanchezValle 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,
Heneka Michael T.,
Jessen Frank,
Matej Radoslav,
Parobkova Eva,
Kovacs Gabor G.,
Ströbel Thomas,
Sarafov Stayko,
Tournev Ivailo,
Jordanova Albena,
Danek Adrian,
Arzberger Thomas,
Fabrizi Gian Maria,
Testi Silvia,
Salmon Eric,
Santens Patrick,
Martin JeanJacques,
Cras Patrick,
Vandenberghe Rik,
De Deyn Peter Paul,
Cruts Marc,
Van Broeckhoven Christine,
van der Zee Julie,
Gijselinck Ilse,
Dillen Lubina,
Van Langenhove Tim,
Theuns Jessie,
Philtjens Stéphanie,
Sleegers Kristel,
Bäumer Veerle,
Maes Githa,
Corsmit Ellen,
Cruts Marc,
Van Broeckhoven Christine,
van der Zee Julie,
Gijselinck Ilse,
Dillen Lubina,
Van Langenhove Tim,
Philtjens Stéphanie,
Theuns Jessie,
Sleegers Kristel,
Bäumer Veerle,
Maes Githa,
Cruts Marc,
Van Broeckhoven Christine,
Engelborghs Sebastiaan,
De Deyn Peter P.,
Cras Patrick,
Engelborghs Sebastiaan,
De Deyn Peter P.,
Vandenbulcke Mathieu,
Vandenbulcke Mathieu,
Borroni Barbara,
Padovani Alessandro,
Archetti Silvana,
Perneczky Robert,
DiehlSchmid Janine,
Synofzik Matthis,
Maetzler Walter,
Müller vom Hagen Jennifer,
Schöls Ludger,
Synofzik Matthis,
Maetzler Walter,
Müller vom Hagen Jennifer,
Schöls Ludger,
Heneka Michael T.,
Jessen Frank,
Ramirez Alfredo,
Kurzwelly Delia,
Sachtleben Carmen,
Mairer Wolfgang,
de Mendonça Alexandre,
MiltenbergerMiltenyi Gabriel,
Pereira Sónia,
Firmo Clara,
Pimentel José,
SanchezValle Raquel,
Llado Albert,
Antonell Anna,
Molinuevo Jose,
Gelpi Ellen,
Graff Caroline,
Chiang HueiHsin,
Westerlund Marie,
Graff Caroline,
Kinhult Ståhlbom Anne,
Thonberg Håkan,
Nennesmo Inger,
BörjessonHanson Anne,
Nacmias Benedetta,
Bagnoli Silvia,
Sorbi Sandro,
Bessi Valentina,
Piaceri Irene,
Santana Isabel,
Santiago Beatriz,
Santana Isabel,
Helena Ribeiro Maria,
Rosário Almeida Maria,
Oliveira Catarina,
Massano João,
Garret Carolina,
Pires Paula,
Frisoni Giovanni,
Zanetti Orazio,
Bonvicini Cristian,
Sarafov Stayko,
Tournev Ivailo,
Jordanova Albena,
Tournev Ivailo,
Kovacs Gabor G.,
Ströbel Thomas,
Heneka Michael T.,
Jessen Frank,
Ramirez Alfredo,
Kurzwelly Delia,
Sachtleben Carmen,
Mairer; Wolfgang,
Jessen Frank,
Matej Radoslav,
Parobkova Eva,
Danel Adrian,
Arzberger Thomas,
Maria Fabrizi Gian,
Testi Silvia,
Ferrari Sergio,
Cavallaro Tiziana,
Salmon Eric,
Santens Patrick,
Cras Patrick
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22244
Subject(s) - trinucleotide repeat expansion , c9orf72 , biology , genetics , allele , haplotype , gene
We assessed the geographical distribution of C9orf72 G 4 C 2 expansions in a pan‐ E uropean frontotemporal lobar degeneration ( FTLD ) cohort ( n = 1,205), ascertained by the E uropean E arly‐ O nset D ementia ( EOD ) consortium. Next, we performed a meta‐analysis of our data and that of other E uropean studies, together 2,668 patients from 15 W estern E uropean countries. The frequency of the C9orf72 expansions in W estern E urope was 9.98% in overall FTLD , with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were F inland and S weden with overall frequencies of respectively 29.33% and 20.73%, but also S pain with 25.49%. In contrast, prevalence in G ermany 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.