Rare variants in RNF213, a susceptibility gene for moyamoya disease, are found in patients with pulmonary hypertension and aggravate hypoxia-induced pulmonary hypertension in mice.
Rare variants in RNF213, a susceptibility gene for moyamoya disease, are found in patients with pulmonary hypertension and aggravate hypoxia-induced pulmonary hypertension in mice.
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DOI：
10.1177/2045894018778155
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发表时间：
2018-07
影响因子：
2.6
通讯作者：
Koizumi A
中科院分区：
文献类型：
--
作者：
Kobayashi H;Kabata R;Kinoshita H;Morimoto T;Ono K;Takeda M;Choi J;Okuda H;Liu W;Harada KH;Kimura T;Youssefian S;Koizumi A
Ring finger 213（RNF 213）是烟雾病（moyamoya disease，MMD）的易感基因。最近的研究表明，RNF 213不仅在MMD中起重要作用，而且在颅外血管疾病如肺动脉高压（PH）中也起重要作用。在这项研究中，我们对PH患者进行了RNF 213的遗传筛查，并使用小鼠模型对RNF 213变体进行了功能分析。在27名日本PH患者中，对RNF 213 C-末端区域的外显子（其中MMD相关突变高度聚集）以及PH的致病基因BMPR 2和CAV 1的整个编码外显子进行直接测序。在2名患者中发现RNF 213中的3个突变（p.R4810K和p.A4399T），在3名患者中发现3个BMPR 2突变（p.Q92H、p.L198Rfs*4和p.S930X），而未发现CAV 1突变。为了测试RNF 213变体对PH的影响，将血管内皮细胞（EC）特异性Rnf 213突变转基因小鼠暴露于缺氧。EC特异性Rnf 213突变体的过表达，但既不是Rnf 213消融也不是EC特异性野生型Rnf 213过表达，加重了缺氧诱导的PH表型（高右心室压力，右心室肥大和肺血管肌化）。缺氧条件下，电子显微镜显示独特的EC脱离肺血管，和蛋白质印迹证明了一个显着减少小窝蛋白-1（CAV 1编码），一个关键分子参与EC功能，在肺EC特异性Rnf 213突变转基因小鼠，提示EC功能障碍。RNF 213似乎是PH的遗传风险因素，并可能在系统性血管病变中发挥作用。
Ring finger 213 (RNF213) is a susceptibility gene for moyamoya disease (MMD), a progressive cerebrovascular disease. Recent studies suggest that RNF213 plays an important role not only in MMD, but also in extracranial vascular diseases, such as pulmonary hypertension (PH). In this study, we undertook genetic screening of RNF213 in patients with PH and performed functional analysis of an RNF213 variant using mouse models. Direct sequencing of the exons in the C-terminal region of RNF213, where MMD-associated mutations are highly clustered, and of the entire coding exons of BMPR2 and CAV1, the causative genes for PH, was performed in 27 Japanese patients with PH. Two MMD-associated rare variants (p.R4810K and p.A4399T) in RNF213 were identified in two patients, three BMPR2 mutations (p.Q92H, p.L198Rfs*4, and p.S930X) were found in three patients, whereas no CAV1 mutations were identified. To test the effect of the RNF213 variants on PH, vascular endothelial cell (EC)-specific Rnf213 mutant transgenic mice were exposed to hypoxia. Overexpression of the EC-specific Rnf213 mutant, but neither Rnf213 ablation nor EC-specific wild-type Rnf213 overexpression, aggravated the hypoxia-induced PH phenotype (high right ventricular pressure, right ventricular hypertrophy, and muscularization of pulmonary vessels). Under hypoxia, electron microscopy showed unique EC detachment in pulmonary vessels, and western blots demonstrated a significant reduction in caveolin-1 (encoded by CAV1), a key molecule involved in EC functions, in lungs of EC-specific Rnf213 mutant transgenic mice, suggestive of EC dysfunction. RNF213 appears to be a genetic risk factor for PH and could play a role in systemic vasculopathy.
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影响因子：
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作者：
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通讯作者：
IKEDA, E
影响因子：
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作者：
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Kobayashi H;Brozman M;Kyselová K;Viszlayová D;Morimoto T;Roubec M;Školoudík D;Petrovičová A;Juskanič D;Strauss J;Halaj M;Kurray P;Hranai M;Harada KH;Inoue S;Yoshida Y;Habu T;Herzig R;Youssefian S;Koizumi A
通讯作者：
Koizumi A