CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study
CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study
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DOI：
10.1016/s1474-4422(14)70266-2
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发表时间：
2015-03-01
期刊：
影响因子：
48
通讯作者：
Hattori, Nobutaka
中科院分区：
文献类型：
--
作者：
Funayama, Manabu;Ohe, Kenji;Hattori, Nobutaka
背景识别孟德尔型帕金森病的致病基因对于了解疾病的病因是有价值的。我们对一个常染色体显性帕金森病的日本家庭进行了基因研究，以确定新的致病基因。方法对常染色体显性帕金森病家族（a家族）的8例患者和5例未患患者进行全基因组连锁分析。随后，我们对三名患者进行了外显子组测序，并对a家族的一名患者进行了全基因组测序，通过Sanger测序在常染色体显性帕金森病患者、散发性帕金森病患者和对照组的样本中验证了变异。参与者从帕金森氏病及相关疾病综合遗传研究（日本东京顺天道大学医学院）的DNA库中识别，并根据神经科医生获得的临床信息进行分类。分析SH-SY5Y细胞中CHCHD2突变体剪接异常。我们使用Fisher精确检验来计算散发性帕金森病患者和未受影响的对照组之间等位基因频率的显著性，并计算了次要等位基因的优势比和95% ci。通过下一代测序，我们在a家族中发现了一个错义突变（CHCHD2, 182C>T, Thr61Ile）。我们从另外340例常染色体显性帕金森病患者、517例散发性帕金森病患者和559例对照患者中获得样本。通过CHCHD2突变筛查，在341例常染色体显性帕金森病独立家族的4例患者中检测到3个CHCHD2突变：182C>T （Thr61Ile）、434G>A （Arg145Gln）和300+5G>A。CHCHD2中两个单核苷酸变异（-9T>G和5C>T）在散发性帕金森病和对照组中有不同的频率，比值比分别为2.51 （95% CI 1.48-4.24; p=0.0004）和4.69 （1.59-13.83,p=0.0025）。在先前报道的全基因组关联研究中，在CHCHD2中发现了一个单核苷酸多态性（rs816411）；然而，在先前报道的全基因组关联研究中，帕金森病患者和对照组之间的频率无显著差异（优势比1-17,95% CI 0.96-1.19; p=0.22）。在SH-SY5Y细胞中，300+5G>A突变而不是其他两个突变引起外显子2跳变。CHCHD2突变与常染色体显性帕金森病相关，并可能是其病因。CHCHD2突变在常染色体显性帕金森病中的致病性和散发性帕金森病的易感性需要在其他人群中进行进一步的遗传学研究，并需要进一步的功能研究来了解CHCHD2突变如何在帕金森病的病理生理中发挥作用。
Background Identification of causative genes in mendelian forms of Parkinson's disease is valuable for understanding the cause of the disease. We did genetic studies in a Japanese family with autosomal dominant Parkinson's disease to identify novel causative genes.Methods We did a genome-wide linkage analysis on eight affected and five unaffected individuals from a family with autosomal dominant Parkinson's disease (family A). Subsequently, we did exome sequencing on three patients and whole-genome sequencing on one patient in family A. Variants were validated by Sanger sequencing in samples from patients with autosomal dominant Parkinson's disease, patients with sporadic Parkinson's disease, and controls. Participants were identified from the DNA bank of the Comprehensive Genetic Study on Parkinson's Disease and Related Disorders (Juntendo University School of Medicine, Tokyo, Japan) and were classified according to clinical information obtained by neurologists. Splicing abnormalities of CHCHD2 mutants were analysed in SH-SY5Y cells. We used the Fisher's exact test to calculate the significance of allele frequencies between patients with sporadic Parkinson's disease and unaffected controls, and we calculated odds ratios and 95% CIs of minor alleles.Findings We identified a missense mutation (CHCHD2, 182C>T, Thr61Ile) in family A by next-generation sequencing. We obtained samples from a further 340 index patients with autosomal dominant Parkinson's disease, 517 patients with sporadic Parkinson's disease, and 559 controls. Three CHCHD2 mutations in four of 341 index cases from independent families with autosomal dominant Parkinson's disease were detected by CHCHD2 mutation screening: 182C>T (Thr61Ile), 434G>A (Arg145Gln), and 300+5G>A. Two single nudeotide variants (-9T>G and 5C>T) in CHCHD2 were confirmed to have different frequencies between sporadic Parkinson's disease and controls, with odds ratios of 2.51 (95% CI 1.48-4.24; p=0.0004) and 4.69 (1.59-13.83, p=0.0025), respectively. One single nucleotide polymorphism (rs816411) was found in CHCHD2 from a previously reported genome-wide association study; however, there was no significant difference in its frequency between patients with Parkinson's disease and controls in a previously reported genome-wide association study (odds ratio 1-17,95% CI 0.96-1.19; p=0.22). In SH-SY5Y cells, the 300+5G>A mutation but not the other two mutations caused exon 2 skipping.Interpretation CHCHD2 mutations are associated with, and might be a cause of, autosomal dominant Parkinson's disease. Further genetic studies in other populations are needed to confirm the pathogenicity of CHCHD2 mutations in autosomal dominant Parkinson's disease and susceptibility for sporadic Parkinson's disease, and further functional studies are needed to understand how mutant CHCHD2 might play a part in the pathophysiology of Parkinson's disease.