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

被引：229

作者：

van der Zee, Julie ^{[1
,2
]}

Gijselinck, Ilse ^{[1
,2
]}

Dillen, Lubina ^{[1
,2
]}

Van Langenhove, Tim ^{[1
,2
]}

Theuns, Jessie ^{[1
,2
]}

Engelborghs, Sebastiaan ^{[2
,3
,4
]}

Philtjens, Stephanie ^{[1
,2
]}

Vandenbulcke, Mathieu ^{[5
,6
]}

Sleegers, Kristel ^{[1
,2
]}

Sieben, Anne ^{[1
,2
,7
,8
]}

Baumer, Veerle ^{[1
,2
]}

Maes, Githa ^{[1
,2
]}

Corsmit, Ellen ^{[1
,2
]}

Borroni, Barbara ^{[9
]}

Padovani, Alessandro ^{[9
]}

Archetti, Silvana ^{[9
]}

Perneczky, Robert ^{[10
]}

Diehl-Schmid, Janine ^{[10
]}

de Mendonca, Alexandre ^{[11
]}

Miltenberger-Miltenyi, Gabriel ^{[11
]}

Pereira, Sonia ^{[11
]}

Pimentel, Jose ^{[12
]}

Nacmias, Benedetta ^{[13
]}

Bagnoli, Silvia ^{[13
]}

Sorbi, Sandro ^{[13
]}

Graff, Caroline ^{[14
,15
]}

Chiang, Huei-Hsin ^{[14
]}

Westerlund, Marie ^{[14
]}

Sanchez-Valle, Raquel ^{[16
]}

Llado, Albert ^{[16
]}

Gelpi, Ellen ^{[17
]}

Santana, Isabel ^{[18
,19
]}

Almeida, Maria Rosario ^{[20
]}

Santiago, Beatriz ^{[18
]}

Frisoni, Giovanni ^{[21
,22
]}

Zanetti, Orazio ^{[21
,22
]}

Bonvicini, Cristian ^{[21
,22
]}

Synofzik, Matthis ^{[23
,24
,25
]}

Maetzler, Walter ^{[23
,24
,25
]}

vom Hagen, Jennifer Mueller ^{[23
,24
,25
]}

Schoels, Ludger ^{[23
,24
,25
]}

Heneka, Michael T. ^{[26
,27
]}

Jessen, Frank ^{[26
,27
,28
]}

Matej, Radoslav ^{[29
]}

Parobkova, Eva ^{[29
]}

Kovacs, Gabor G. ^{[30
]}

Stroebel, Thomas ^{[30
]}

Sarafov, Stayko ^{[31
]}

Tournev, Ivailo ^{[31
,32
]}

Jordanova, Albena ^{[1
,33
]}

机构：

[1] Univ Antwerp VIB, Dept Mol Genet, B-2610 Antwerp, Belgium

[2] Univ Antwerp, Inst Born Bunge, B-2020 Antwerp, Belgium

[3] Hosp Network Antwerp Middelheim & Hoge Beuken, Dept Neurol, Antwerp, Belgium

[4] Hosp Network Antwerp Middelheim & Hoge Beuken, Memory Clin, Antwerp, Belgium

[5] Univ Louvain, Dept Psychiat, Brain & Emot Lab Leuven, Louvain, Belgium

[6] Univ Hosp Leuven Gasthuisberg, Louvain, Belgium

[7] Univ Hosp Ghent, Dept Neurol, Ghent, Belgium

[8] Univ Ghent, B-9000 Ghent, Belgium

[9] Univ Brescia, Neurol Unit, Ctr Ageing Brain & Neurodegenerat Disorders, Brescia, Italy

[10] Tech Univ Munich, Dept Psychiat & Psychotherapy, D-80290 Munich, Germany

[11] Univ Lisbon, Inst Mol Med, Fac Med, P-1699 Lisbon, Portugal

[12] Univ Lisbon, Fac Med, P-1699 Lisbon, Portugal

[13] Univ Florence, Dept Neurol & Psychiat Sci, Florence, Italy

[14] Karolinska Inst, Dept Neurobiol Care Sci & Soc, KI Alzheimer Dis Res Ctr, Stockholm, Sweden

[15] Karolinska Univ Hosp, Genet Unit, Dept Geriatr Med, Stockholm, Sweden

[16] Hosp Clin Barcelona, Dept Neurol, Alzheimers Dis & Other Cognit Disorders Unit, Barcelona, Spain

[17] Hosp Clin Barcelona, IDIBAPS, Barcelona, Spain

[18] Ctr Hosp Univ Coimbra, Dept Neurol, Coimbra, Portugal

[19] Univ Coimbra, Fac Med, Coimbra, Portugal

[20] Univ Coimbra, Ctr Neurosci & Cell Biol, Coimbra, Portugal

[21] FBF, IRCCS Ctr San Giovanni di Dio, Lab Epidemiol Neuroimaging & Telemed, Brescia, Italy

[22] FBF, IRCCS Ctr San Giovanni di Dio, Natl Ctr Alzheimers & Mental Dis, Brescia, Italy

[23] Hertie Inst Clin Brain Res, Dept Neurodegenerat, Tubingen, Germany

[24] Ctr Neurol, Tubingen, Germany

[25] Univ Tubingen, German Res Ctr Neurodegenerat Dis DZNE, Tubingen, Germany

[26] Univ Bonn, Dept Neurol, Clin Neurosci Unit, Bonn, Germany

[27] Univ Bonn, German Ctr Neurodegenerat Dis DZNE, Bonn, Germany

[28] Univ Bonn, Dept Psychiat, Bonn, Germany

[29] Thomayer Hosp, Dept Pathol & Mol Med, Prague, Czech Republic

[30] Med Univ Vienna, Inst Neurol, Vienna, Austria

[31] Med Univ Sofia, Dept Neurol, Sofia, Bulgaria

[32] New Bulgarian Univ, Dept Cognit Sci & Psychol, Sofia, Bulgaria

[33] Med Univ, Dept Biochem, Mol Med Ctr, Sofia, Bulgaria

[34] Univ Munich, Neurol Klin, Munich, Germany

[35] Univ Munich, Zentrum Neuropathol & Prionforsch, Munich, Germany

[36] Univ Verona, Sect Neuropathol, Dept Neurol Neuropsychol Morphol & Movement Sci, I-37100 Verona, Italy

[37] Univ Liege, Cyclotron Res Ctr, Liege, Belgium

[38] Univ Liege, Dept Neurol, Liege, Belgium

[39] Univ Antwerp Hosp, Dept Neurol, Edegem, Belgium

[40] Univ Louvain, Dept Neurol, Lab Cognit Neurol, Louvain, Belgium

来源：

HUMAN MUTATION | 2013年 / 34卷 / 02期

基金：

瑞典研究理事会;

关键词：

FTLD; C9orf72; repeat expansion; intermediate alleles; European Early-Onset Dementia consortium; AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; GGGGCC HEXANUCLEOTIDE REPEAT; PATHOLOGICAL FEATURES; EXPANSION; DEMENTIA; SUSCEPTIBILITY; MUTATION; LOCUS; GENE;

D O I：

10.1002/humu.22244

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：363 / 373

页数：11

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