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Recent studies suggest that <jats:italic>RNF213<\/jats:italic> 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 <jats:italic>RNF213<\/jats:italic> in patients with PH and performed functional analysis of an <jats:italic>RNF213<\/jats:italic> variant using mouse models. Direct sequencing of the exons in the C\u2010terminal region of <jats:italic>RNF213<\/jats:italic>, where MMD\u2010associated mutations are highly clustered, and of the entire coding exons of <jats:italic>BMPR2<\/jats:italic> and <jats:italic>CAV1<\/jats:italic>, the causative genes for PH, was performed in 27\u00a0Japanese patients with PH. Two MMD\u2010associated rare variants (p.R4810K and p.A4399T) in <jats:italic>RNF213<\/jats:italic> were identified in two patients, three <jats:italic>BMPR2<\/jats:italic> mutations (p.Q92H, p.L198Rfs*4, and p.S930X) were found in three patients, whereas no <jats:italic>CAV1<\/jats:italic> mutations were identified. To test the effect of the <jats:italic>RNF213<\/jats:italic> variants on PH, vascular endothelial cell (EC)\u2010specific <jats:italic>Rnf213<\/jats:italic> mutant transgenic mice were exposed to hypoxia. Overexpression of the EC\u2010specific <jats:italic>Rnf213<\/jats:italic> mutant, but neither <jats:italic>Rnf213<\/jats:italic> ablation nor EC\u2010specific wild\u2010type <jats:italic>Rnf213<\/jats:italic> overexpression, aggravated the hypoxia\u2010induced 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\u20101 (encoded by <jats:italic>CAV1<\/jats:italic>), a key molecule involved in EC functions, in lungs of EC\u2010specific <jats:italic>Rnf213<\/jats:italic> mutant transgenic mice, suggestive of EC dysfunction. <jats:italic>RNF213<\/jats:italic> appears to be a genetic risk factor for PH and could play a role in systemic vasculopathy.<\/jats:p>","DOI":"10.1177\/2045894018778155","type":"journal-article","created":{"date-parts":[[2018,5,2]],"date-time":"2018-05-02T19:17:31Z","timestamp":1525288651000},"page":"1-13","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":48,"title":["Rare variants in <i>RNF213<\/i>, a susceptibility gene for moyamoya disease, are found in patients with pulmonary hypertension and aggravate hypoxia\u2010induced pulmonary hypertension in 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