A heterozygous effect for PINK1 mutations in Parkinson's disease?
A heterozygous effect for PINK1 mutations in Parkinson's disease?
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DOI：
10.1002/ana.20960
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发表时间：
2006-10-01
影响因子：
11.2
通讯作者：
Wood, Nicholas W.
中科院分区：
文献类型：
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作者：
Abou-Sleiman, Patrick M.;Muqit, Miratul M. K.;Wood, Nicholas W.
目的：研究PINK 1突变在散发性帕金森病（PD）中的意义。方法：我们通过直接测序确定了大量散发性PD患者（n = 768）的PINK 1突变频率。结果：鉴定了12个杂合突变，其中9个在PD患者中，3个在对照组中。解释：考虑到解释parkin和DJ-1中已经报道的杂合突变的致病意义的困难，我们首先通过对大量的对照受试者（n = 10）进行测序，确定了普通人群中杂合PINK 1突变的频率。768），随后通过检查它们对应激诱导的线粒体膜电位（Δ psi m）改变的影响来评估它们的功能意义。我们证明了与匹配的对照受试者相比，散发性PD患者中杂合突变的富集（PD为1.2%，对照为0.4%）。此外，我们表明，他们不利地影响三角洲psi米以类似的方式对家族性G309 D突变。虽然仍然难以最终证明杂合突变的致病性，但本研究的结果和先前报道的杂合PINK 1突变携带者的亚临床黑质纹状体功能障碍表明，这些杂合突变可能是晚发型PD发生的重要风险因素。
Objective: To investigate the significance of PINK1 mutations in sporadic Parkinson's disease (PD).Methods: We determined the frequency of PINK1 mutations by direct sequencing in a large series of PD patients with apparently sporadic disease (n = 768).Results: Twelve heterozygous mutations were identified, nine in PD patients and three in control subjects.Interpretation: Given the difficulty in interpreting the pathogenic significance of the heterozygous mutations that have already been reported in parkin and DJ-1, we first determined the frequency of heterozygous PINK1 mutations in the general population by sequencing a large number of control subjects (n = 768), then subsequently assessed their functional significance by examining their effects on stress-induced alterations to the mitochondrial membrane potential (Delta psi m). We demonstrate an enrichment of heterozygous mutations in sporadic PD patients compared with matched control subjects (1.2% in PD vs 0.4% in control subjects). Furthermore, we show that they adversely affect Delta psi m in a similar way to the familial G309D mutation. Although it remains difficult to conclusively demonstrate the pathogenicity of heterozygous mutations, the results of this study and the previously reported subdinical nigrostriatal dysfunction in carriers of heterozygous PINK1 mutations suggest the possibility that these heterozygous mutations are a significant risk factor in the development of later onset PD.