Genetic variability in the mitochondrial serine protease HTRA2 contributes to risk for Parkinson disease
Genetic variability in the mitochondrial serine protease HTRA2 contributes to risk for Parkinson disease
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DOI：
10.1002/humu.20713
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发表时间：
2008-06-01
期刊：
影响因子：
3.9
通讯作者：
Van Broeckhoven, Christine
中科院分区：
文献类型：
--
作者：
Bogaerts, Veerle;Nuytemans, Karen;Van Broeckhoven, Christine
在一项基因研究中，高温需求 A2 (HTRA2) 线粒体蛋白与散发性帕金森病 (PD) 的风险增加有关。其 C 端 PDZ 结构域中的一种错义突变 p.Gly399Ser（来自突触后密度 95 的首字母，PSD-95；椎间盘大；和小带闭塞-1，ZO-1 蛋白 [Kennedy，1995]）导致蛋白酶激活缺陷，并在稳定转染的细胞中过度表达时诱导线粒体功能障碍。在这里，我们在 266 名比利时 PD 患者和 273 名对照个体的扩展系列中检查了 HTRA2 遗传变异对 PD 风险的影响。突变分析发现 PDZ 结构域内有一个新的 p.Arg404Trp 突变，预计会以非活性形式冻结 HTRA2。此外，我们还确定了六名患者。 5' 和 3' 调控区的特定变异可能影响 HTRA2 表达，如荧光素酶报告基因分析数据所支持。我们的研究通过其功能性 PDZ 结构域的突变证实了 HTRA2 线粒体蛋白在 PD 易感性中的作用。此外，它将 HTRA2 突变谱扩展到可能影响转录活性的功能变异。后者支持了之前未被认识到的 HTRA2 表达改变作为帕金森神经变性相关危险因素的作用。
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.