A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2
A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2
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DOI：
10.1212/wnl.0b013e3181f4d832
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发表时间：
2010-09-01
期刊：
影响因子：
9.9
通讯作者：
Payami, H.
中科院分区：
文献类型：
--
作者：
Kay, D. M.;Stevens, C. F.;Payami, H.
目的：对PARK2进行全面的群体遗传研究。PARK2突变与青少年帕金森病、阿尔茨海默病、癌症、麻风病和糖尿病有关，但具有讽刺意味的是，在对照受试者中尚无PARK2的全面研究；并在一项强有力的研究中解决PARK2杂合突变与帕金森病（PD）之间存在争议的关联。方法：我们研究了1,686名对照组（平均年龄66.1 +/- 13.1岁）和2,091名PD患者（平均发病年龄58.3 +/- 12.1岁）。我们使用半定量PCR和多重连接依赖探针扩增检测了PARK2缺失/复制/拷贝数变异（CNV），并通过实时定量PCR验证了突变。之前对受试者进行了点突变测试。与帕金森病的关联被测试为PARK2的主要作用，并结合已知的帕金森病危险因素：SNCA、MAPT、APOE、吸烟和咖啡摄入。结果：共有0.95%的对照组和0.86%的患者携带杂合CNV突变。在16个对照组中发现的CNV突变都位于外显子1-4，保留了编码功能关键蛋白结构域的外显子。2个CNV突变13例，1个CNV和1个点突变5例，1个CNV突变18例。在患者中发现的突变跨越2-9外显子。在白人中，拥有1个CNV与PD风险增加（优势比1.05,p = 0.89）或早期发病无关（杂合子64.7 +/- 8.6 vs正常58.5 +/- 11.8）。结论：本研究对对照人群进行了全面的群体遗传研究，填补了PARK2参考数据集的空白。没有令人信服的证据表明杂合子PARK2突变本身或与已知危险因素相结合与帕金森病有关。神经病学(R) 2010；75: 1189 - 1194
Objectives: To perform a comprehensive population genetic study of PARK2. PARK2 mutations are associated with juvenile parkinsonism, Alzheimer disease, cancer, leprosy, and diabetes mellitus, yet ironically, there has been no comprehensive study of PARK2 in control subjects; and to resolve controversial association of PARK2 heterozygous mutations with Parkinson disease (PD) in a well-powered study.Methods: We studied 1,686 control subjects (mean age 66.1 +/- 13.1 years) and 2,091 patients with PD (mean onset age 58.3 +/- 12.1 years). We tested for PARK2 deletions/multiplications/copy number variations (CNV) using semiquantitative PCR and multiplex ligation-dependent probe amplification, and validated the mutations by real-time quantitative PCR. Subjects were tested for point mutations previously. Association with PD was tested as PARK2 main effect, and in combination with known PD risk factors: SNCA, MAPT, APOE, smoking, and coffee intake.Results: A total of 0.95% of control subjects and 0.86% of patients carried a heterozygous CNV mutation. CNV mutations found in 16 control subjects were all in exons 1-4, sparing exons that encode functionally critical protein domains. Thirteen patients had 2 CNV mutations, 5 had 1 CNV and 1 point mutation, and 18 had 1 CNV mutation. Mutations found in patients spanned exons 2-9. In whites, having 1 CNV was not associated with increased risk (odds ratio 1.05, p = 0.89) or earlier onset of PD (64.7 +/- 8.6 heterozygous vs 58.5 +/- 11.8 normal).Conclusions: This comprehensive population genetic study in control subjects fills the void for a PARK2 reference dataset. There is no compelling evidence for association of heterozygous PARK2 mutations, by themselves or in combination with known risk factors, with PD. Neurology (R) 2010; 75: 1189-1194