Genetic variability in the mitochondrial serine protease HTRA2 contributes to risk for Parkinson disease

被引:78
作者
Bogaerts, Veerle [2 ,3 ]
Nuytemans, Karen [2 ,3 ]
Reumers, Joke [4 ]
Pals, Philippe [3 ,5 ,6 ]
Engelborghs, Sebastiaan [3 ,7 ,8 ,9 ]
Pickut, Barbara [8 ,9 ]
Corsmit, Ellen [2 ,3 ]
Peeters, Karin [2 ,3 ]
Schymkowitz, Joost [4 ]
De Deyn, Peter Paul [3 ,7 ,8 ,9 ]
Cras, Patrick [3 ,5 ,6 ]
Rousseau, Frederic [4 ]
Theuns, Jessie [2 ,3 ]
Van Broeckhoven, Christine [1 ,2 ,3 ]
机构
[1] Univ Antwerp VIB, Neurodegenerat Brain Dis Grp, Dept Mol Genet, CDE, BE-2610 Antwerp, Belgium
[2] Inst Born Bunge, Neurogenet Lab, Antwerp, Belgium
[3] Univ Antwerp, B-2020 Antwerp, Belgium
[4] Vrije Univ Brussel VIB, SWITCH Lab, B-1050 Brussels, Belgium
[5] Inst Born Bunge, Neurobiol Lab, Antwerp, Belgium
[6] Univ Antwerp Hosp, Div Neurol, Antwerp, Belgium
[7] Inst Born Bunge, Lab Neurochem & Behav, Antwerp, Belgium
[8] Memory Clin, Antwerp, Belgium
[9] ZNA Middelheim, Div Neurol, Antwerp, Belgium
关键词
HTRA2; high temperature requirement protein A2; mitochondrial serine protease; Parkinson disease; regulatory variants;
D O I
10.1002/humu.20713
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
In one genetic study, the high temperature requirement A2 (HTRA2) mitochondrial protein has been associated with increased risk for sporadic Parkinson disease (PD). One missense mutation, p.Gly399Ser, in its C-terminal PDZ domain (from the initial letters of the postsynaptic density 95, PSD-95; discs large; and zonula occludens-1, ZO-1 proteins [Kennedy, 1995]) resulted in defective protease activation, and induced mitochondrial dysfunction when overexpressed in stably transfected cells. Here we examined the contribution of genetic variability in HTRA2 to PD risk in an extended series of 266 Belgian PD patients and 273 control individuals. Mutation analysis identified a novel p.Arg404Trp mutation within the PDZ domain predicted to freeze HTRA2 in an inactive form. Moreover, we identified six patient. specific variants in 5' and 3' regulatory regions that might affect HTRA2 expression as supported by data of luciferase reporter gene analyses. Our study confirms a role of the HTRA2 mitochondrial protein in PD susceptibility through mutations in its functional PDZ domain. In addition, it extends the HTRA2 mutation spectrum to functional variants possibly affecting transcriptional activity. The latter underpins a previously unrecognized role for altered HTRA2 expression as a risk factor relevant to parkinsonian neurodegeneration.
引用
收藏
页码:832 / 840
页数:9
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