Exome Sequencing Identified CCER2 as a Novel Candidate Gene for Moyamoya Disease
Exome Sequencing Identified CCER2 as a Novel Candidate Gene for Moyamoya Disease
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DOI：
10.1016/j.jstrokecerebrovasdis.2016.09.003
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发表时间：
2017-01-01
影响因子：
2.5
通讯作者：
Akagawa, Hiroyuki
中科院分区：
文献类型：
--
作者：
Mukawa, Maki;Nariai, Tadashi;Akagawa, Hiroyuki
烟雾病（MMD）的病因仍不清楚，尽管RNF 213是东亚患者最重要的易感基因。继我们先前的研究证实了日本MMD患者的遗传异质性之后，我们广泛调查了新的候选基因，以获得对这种疾病病因的新观点。选择两个在RNF 213中没有易感性变体的特征性家系进行全外显子组测序; 1个携带3个受影响的成员，另一个包括不一致的单卵双胞胎。在前一个家系中，12个基因的12个罕见突变与MMD共分离。其中最有害的氨基酸变化之一是CCER 2中的p.T76_G80delinsPS，其在后一个家系中也发生了突变（p.E242K），尽管未受影响的孪生姐妹具有相同的突变，反映了降低的染色体畸变率。使用计算机功能分析，预测这些CCER 2突变促进其蛋白产物的聚集或寡聚化。随后在另外135名MMD先证者中进行CCER 2重新测序，鉴定出1个复发性和另外2个框内插入-缺失突变，复发性p.T76_G80delinsPS、p.H218_H220del和p.E299del。虽然CCER 2的分子功能尚未得到很好的表征，但它是在脑中表达的分泌蛋白;因此，它构成了MMD的潜在生物标志物。(C)2017年全国中风协会。爱思唯尔公司出版All rights reserved.
The etiology of Moyamoya disease (MMD) is still largely unclear, despite identification of RNF213 as the most significant susceptibility gene in East Asian patients. Following up our previous study confirming genetic heterogeneity in Japanese patients with MMD, we extensively surveyed novel candidate genes for a new perspective on the etiology of this disease. Two characteristic pedigrees without susceptibility variants in RNF213 were selected for whole-exome sequencing; 1 harbored 3 affected members, and the other included discordant monozygotic twins. In the former pedigree, 12 rare mutations in 12 genes were co-segregated with MMD. One of the most deleterious amino acid changes among these was p.T76_G80delinsPS in CCER2, which was also mutated in the latter pedigree (p.E242K), although the unaffected twin sister shared the same mutation reflecting reduced penetrance. These CCER2 mutations were predicted to promote aggregation or oligomerization of their protein product, using in silico functional analysis. Subsequent CCER2 re-sequencing in an additional 135 MMD probands identified 1 recurrent and an additional 2 in-frame insertion-deletion mutations, recurrent p.T76_G80delinsPS, p.H218_H220del, and p.E299del. Although CCER2 molecular function is not well characterized, it is a secretory protein expressed in the brain; therefore, it constitutes a potential biomarker of MMD. (C) 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.