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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.

ABSTRACT: 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.

SUBMITTER: Kobayashi H

PROVIDER: S-EPMC5991195 | biostudies-literature | 2018 Jul-Sep

REPOSITORIES: biostudies-literature

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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.

Kobayashi Hatasu H Kabata Risako R Kinoshita Hideyuki H Morimoto Takaaki T Ono Koh K Takeda Midori M Choi Jungmi J Okuda Hiroko H Liu Wanyang W Harada Kouji H KH Kimura Takeshi T Youssefian Shohab S Koizumi Akio A

Pulmonary circulation 20180502 3

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 M ...[more]

PMID: 29718794

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Project description:BACKGROUND:The p.R4810K and other rare variants of ring finger protein 213 gene (RNF213) were illustrated as susceptibility variants for moyamoya (MMD) and non-moyamoya intracranial artery stenosis/occlusion disease (ICASO) recently. However, the effect sizes of p.R4810K were in great discrepancy even in studies of the same ethnic population and firm conclusions of other rare variants have been elusive given the small sample sizes and lack of replication. Thus, we performed this study to quantitatively evaluate whether or to what extent the rare variants of RNF213 contribute to MMD and ICASO in different populations. METHODS:A systematic search of PubMed, EMBASE, ISI web of science, CNKI, and WANFANG DATA was conducted up to 5 September 2017. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random- or fixed-effect models based on the between-study heterogeneity. The subgroup analyses were performed by the ethnicity and family history. Sensitivity and publication bias analysis were performed to test the robustness of associations. All the statistical analyses were conduct using STATA 12.0. RESULTS:Twenty studies including 2353 MMD cases and 5488 controls and 11 studies including 1778 ICASO cases and 3140 controls were included in this study. Pooled ORs indicated that RNF213 p.R4810K significantly increased MMD and ICASO risk in East Asians with great effect sizes of discrepancy (dominant model: odds ratios 184.04, 109.77, and 31.53 and 10.07, 28.52, and 5.59 for MMD and ICASO, respectively, in Japan, Korea, and China). It significantly increased familial MMD risk in Japan, Korea, and China with 5 ~ 36 times larger effect sizes than that for sporadic ones in each country (dominant model ORs 1802.44, 512.42, 1109.02 and 134.35, 99.82, and 30.52, respectively, for familial and sporadic cases). The effect sizes of RNF213 p.R4810K to sporadic MMD were 3 ~ 4 times larger in Japan and Korea than those in China. RNF213 p.R4810K also increased the ICASO risk in Japan and Korea with 2 ~ 4 times larger effect sizes than that in China (dominant model ORs 10.71, 28.52, and 5.59, respectively). Another two rare variants- p.E4950D and p.A5021V significantly increased MMD risk in Chinese population (dominant model ORs 9.06 and 5.01, respectively). Various other rare variants in RNF213 were identified in Japanese, Chinese, European, and Hispanic American populations without association evidence available yet. CONCLUSIONS:This meta-analysis shows the critical roles of RNF213 p.R4810K in MMD especially familial MMD and ICASO in Japan, Korea, and China. Except for RNF213 p.R4810K, MMD seems to have more complex determiners in China. Distinct genetic background exists and other environmental or genetic factor(s) may contribute to MMD. Studies focused on delineating the ethnicity-specific factors and pathological role of RNF213 variants in MMD and ICASO are needed.

Project description:ImportanceIdiopathic pulmonary arterial hypertension (IPAH) is a fatal disease with high heritability; however, the bone morphogenetic protein receptor 2 (BMPR2) gene only accounts for 17% of IPAH. The genetic basis of IPAH needs further investigation.ObjectiveTo identify novel IPAH susceptibility genes other than BMPR2.Design, setting, and participantsThis 2-stage, case-control genetic association study enrolled 230 patients with IPAH from 2 referral pulmonary hypertension centers in China. Eligible patients had no BMPR2 variants and were compared with 968 healthy control participants. Data were collected from January 1, 2000, to July 31, 2015, and analyzed from August 1, 2015, to May 30, 2018.ExposuresPTGIS rare variants.Main outcomes and measuresWhole-genome sequencing was performed to identify putative IPAH genes in a discovery cohort, with validation in an independent referral cohort. Correlation of genotype and hemodynamic characteristics was then evaluated at baseline and after pulmonary vasodilator testing. Functional assessments were conducted to analyze the effects of identified genetic variants on transcript splicing, enzymatic activity, and endothelial cell phenotypes.ResultsAmong 230 patients with IPAH (164 female [71.3%]; mean [SD] age, 34 [18] years), an enrichment of rare variants in a gene encoding prostacyclin synthase (PTGIS) was identified in the discovery cohort. The association of PTGIS rare variants with IPAH was confirmed in the replication cohort. In the combined data set, PTGIS rare variants were found in 14 of 230 cases (6.1%) and 8 of 968 controls (0.8%) (odds ratio, 7.8; 95% CI, 3.2-18.8; P = 5 × 10-6, logistic regression). Compared with patients without PTGIS variants, inhaled iloprost induced a more significant decrease of pulmonary vascular resistance (difference in the least square mean, -21.7%; 95% CI, -31.4% to -12.0%; P < .001, linear regression model) and an increase of cardiac index (difference in the least square mean, 18.3%; 95% CI, 8.8%-27.8%; P < .001, linear regression model) in patients with PTGIS variants. The minigene assay indicated that the c.521 + 1G>A variant resulted in aberrant messenger RNA transcripts. The functional studies showed that the 2 missense rare variants (R252Q and A447T) resulted in a decrease in prostacyclin production and increased cell death of pulmonary microvascular endothelial cells.Conclusions and relevanceThis study identified 3 rare loss-of-function variants in the PTGIS gene from 2 independent cohorts with IPAH. The genetic variants of PTGIS predispose pulmonary vascular responses to the iloprost stimulation. These findings suggest that PTGIS variants may be involved in the pathogenesis of IPAH.

Dataset Information

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.

Publications

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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