Mutations Other Than Null Mutations Producing a Pathogenic Loss of Progranulin in Frontotemporal Dementia

被引：96

作者：

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

Le Ber, Isabelle ^{[9
,10
,11
]}

Maurer-Stroh, Sebastian ^{[19
]}

Engelborghs, Sebastiaan ^{[3
,5
]}

Gijselinck, Ilse ^{[1
,2
]}

Camuzat, Agnes ^{[14
]}

Brouwers, Nathalie ^{[1
,2
]}

Vandenberghe, Rik ^{[6
,7
]}

Sleegers, Kristel ^{[1
]}

Hannequin, Didier ^{[2
]}

Dermaut, Bart ^{[15
]}

Schymkowitz, Joost ^{[8
]}

Campion, Dominique ^{[19
]}

Santens, Patrick ^{[16
]}

Martin, Jean-Jacques ^{[8
]}

Lacomblez, Lucette ^{[4
]}

De Pooter, Tim ^{[10
,12
,18
]}

Peeters, Karin ^{[1
,2
]}

Mattheijssens, Maria ^{[1
,2
]}

Vercelletto, Martine ^{[17
]}

Van den Broeck, Marleen ^{[1
,2
]}

Cruts, Marc ^{[1
,2
]}

De Deyn, Peter P. ^{[3
,5
]}

Rousseau, Frederic ^{[19
]}

Brice, Alexis ^{[9
,10
,12
,13
]}

Van Broeckhoven, Christine ^{[1
,2
]}

机构：

[1] Univ Antwerp, CDE, VIB,Dept Mol Genet, Neurodegenerat Brain Dis Grp, BE-2610 Antwerp, Belgium

[2] Univ Antwerp, Lab Neurogenet, BE-2610 Antwerp, Belgium

[3] Univ Antwerp, Lab Neurochem & Behav, BE-2610 Antwerp, Belgium

[4] Univ Antwerp, Inst Born Bunge, Lab Neuropathol, BE-2610 Antwerp, Belgium

[5] Middelheim Hosp, Div Neurol, Mem Clin, Antwerp, Belgium

[6] Katholieke Univ Leuven, Univ Hosp Gasthuisberg, Dept Neurol, Louvain, Belgium

[7] Katholieke Univ Leuven, Univ Hosp Gasthuisberg, Dept Neuropathol, Louvain, Belgium

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

[9] INSERM, U679, Paris, France

[10] AP HP, Hop Pitie Salpetriere, Fed Maladies Syst Nerveux, Paris, France

[11] AP HP, Hop Pitie Salpetriere, Ctr Neuropsychol & Langage, Paris, France

[12] Univ Paris 06, Fac Med, Paris, France

[13] AP HP, Hop Pitie Salpetriere, Dept Genet Cytogenet & Embryol, Paris, France

[14] Hop La Pitie Salpetriere, INSERM, U679, Paris, France

[15] Rouen Univ Hosp, INSERM, U614, Rouen, France

[16] Rouen Univ Hosp, Dept Neurol, Rouen, France

[17] CHU Guillaume & Rene Laennec, Serv Neurol, Nantes, France

[18] Hop La Pitie Salpetriere, Serv Pharmacol, Paris, France

[19] Free Univ Brussels, VIB, SWITCH Lab, Brussels, Belgium

来源：

HUMAN MUTATION | 2007年 / 28卷 / 04期

关键词：

GRN; PGRN; progranulin; frontotemporal dementia; 17q21; ubiquitin-positive inclusions; PGRN missense mutations; PGRN 5' sequence variations;

D O I：

10.1002/humu.9484

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Null mutations in the progranulin gene (GRN, PGRN) were recently identified as the causal mechanism underlying frontotemporal dementia (FTD) with ubiquitin-positive brain pathology linked to chromosome 17 (FTDU-17). In a Belgian and French FTD series comprising 332 patients, we reported 13 PGRN null mutations which were mainly nonsense and frameshift mutations resulting in premature stop codons. Here we report in the same patient series three missense mutations of which two (c.743C>T, p.Pro248Leu and c.1294C>T, p.Arg432Cys) were predicted in silico to severely affect protein folding and/or processing leading to PGRN protein haploinsufficiency. In addition, we observed three sequence variations in the 5' regulatory region that might potentially affect PGRN transcription activity. Our findings extend the mutation spectrum in PGRN leading to loss of functional PGRN as the basis for FTD. (C) 2007 Wiley-Liss, Inc.

引用

页码：416 / 416

页数：1

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