全基因组测序：揭示多系统萎缩的突变基因

据《New England Journal of Medicine》报道：COQ2功能受损的变异基因，这个变异基因可以编码对羟苯甲酸-聚丙烯转移酶，这个基因在多系统萎缩患者的多个家庭中及一些散发病的患者中被发现。

来自东京大学的Jun Mitsui和他的同事们通过全基因组测序患者的标本，并对5个家庭的样本进行了突变分析及羟苯甲酸-聚丙烯转移酶活性的测量。

在两个家庭中，研究员发现一个纯合体的突变（M78V-V343A/M78V-V343A）及在COQ2基因中发现复合杂合基因的突变（R337X/V343A）。一个共同的突变（V343A）及多种罕见的突变也在COQ2中发现，所有这些基因突变导致COQ2功能性的损伤，与散发性的多系统萎缩相关。突变子V343A仅仅在日本人中发现。

作者表示：“这项研究发现功能性基因COQ2的损伤与多系统萎缩风险的增加有关，并提供了证据表明COQ2在这个疾病的发生过程中涉及的病理生理机制。”


原文链接：

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Mutations in COQ2 in Familial and Sporadic Multiple-System Atrophy

BackgroundMultiple-system atrophy is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Although multiple-system atrophy is widely considered to be a nongenetic disorder, we previously identified multiplex families with this disease, which indicates the involvement of genetic components.

MethodsIn combination with linkage analysis, we performed whole-genome sequencing of a sample obtained from a member of a multiplex family in whom multiple-system atrophy had been diagnosed on autopsy. We also performed mutational analysis of samples from members of five other multiplex families and from a Japanese series (363 patients and two sets of controls, one of 520 persons and one of 2383 persons), a European series (223 patients and 315 controls), and a North American series (172 patients and 294 controls). On the basis of these analyses, we used a yeast complementation assay and measured enzyme activity of parahydroxybenzoate-polyprenyl transferase. This enzyme is encoded by the gene COQ2 and is essential for the biosynthesis of coenzyme Q10. Levels of coenzyme Q10 in lymphoblastoid cells and brain tissue were measured on high-performance liquid chromatography.

ResultsWe identified a homozygous mutation (M78V-V343A/M78V-V343A) and compound heterozygous mutations (R337X/V343A) in COQ2 in two multiplex families. Furthermore, we found that a common variant (V343A) and multiple rare variants in COQ2, all of which are functionally impaired, are associated with sporadic multiple-system atrophy. The V343A variant was exclusively observed in the Japanese population.

ConclusionsFunctionally impaired variants of COQ2 were associated with an increased risk of multiple-system atrophy in multiplex families and patients with sporadic disease, providing evidence of a role of impaired COQ2 activities in the pathogenesis of this disease. (Funded by the Japan Society for the Promotion of Science and others.)