Pulmonary artery hypertension (PAH) is characterized as sustained elevation of pressure in the pulmonary vascular system that is attributable to a variety of causes. More than a dozen genes have previously been proposed as being associated with PAH. To examine potential mutations of these genes in patients with PAH, we developed a targeted exome kit containing 22 PAH-associated genes for genetic screens of 80 unrelated patients with PAH. As a result, we identified 16 different mutations in the BMPR2 gene and four different mutations in ACVRL1, the gene for activin receptor-like kinase-1 (ACVRL1). However, no deleterious mutations were found in the remaining 20 genes. In the present study, we provided detailed characterization of the ACVRL1 mutations in four pedigrees, including two novel missense mutations (c.676G>A, p.V226M; c.955G>C, p.G319R) and two recurrent mutations (c.1231C>T, p.R411W; c.1450C>T, p.R484W). Furthermore, we showed that markedly reduced Smad1/5 phosphorylation levels and reduced activities of luciferase reporters in each of the four ACVRL1 mutant-transfected NIH-3T3 cells. Therefore, our findings demonstrated that missense mutations of ACVRL1 identified in the present study significantly affected the bone morphogenetic protein 9 (BMP-9) pathway, implicating PAH pathogenesis. Detailed genotype–phenotype correlation analysis revealed initial symptoms of hereditary haemorrhagic telangiectasia (HHT) in some of the patients, suggesting the importance of sequencing molecular markers for early identification and intervention of individuals at risk for PAH and potential HHT. We developed a customized exome sequencing system to identify mutations in these PAH-associated genes, and found two novel missense mutations and two recurrent mutations in the ACVRL1 gene in four unrelated Chinese families; we also determined hypomorphic alleles using functional studies.
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Corin protein expression in human renal proximal convoluted tubules as shown by brown staining in immunohistochemistry. See pp. 1655-1664 for further details. Image kindly provided by Qingyu Wu.
Research Article|
July 28 2016
Identification of multiple ACVRL1 mutations in patients with pulmonary arterial hypertension by targeted exome capture
Chunmei Piao;
Chunmei Piao
1
*Beijing Anzhen Hospital, Capital Medical University, Beijing, China
†Beijing Collaborative Innovation Centre for Cardiovascular Disorders, Beijing, China
‡The Key Laboratory of Remodelling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing 100029, China
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Yan Zhu;
Yan Zhu
1
§Department of Paediatric Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
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Chen Zhang;
Chen Zhang
1
§Department of Paediatric Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
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Xin Xi;
Xin Xi
*Beijing Anzhen Hospital, Capital Medical University, Beijing, China
†Beijing Collaborative Innovation Centre for Cardiovascular Disorders, Beijing, China
‡The Key Laboratory of Remodelling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing 100029, China
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Xuxia Liu;
Xuxia Liu
*Beijing Anzhen Hospital, Capital Medical University, Beijing, China
†Beijing Collaborative Innovation Centre for Cardiovascular Disorders, Beijing, China
‡The Key Laboratory of Remodelling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing 100029, China
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Shuai Zheng;
Shuai Zheng
*Beijing Anzhen Hospital, Capital Medical University, Beijing, China
†Beijing Collaborative Innovation Centre for Cardiovascular Disorders, Beijing, China
‡The Key Laboratory of Remodelling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing 100029, China
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Xiaoyan Li;
Xiaoyan Li
*Beijing Anzhen Hospital, Capital Medical University, Beijing, China
†Beijing Collaborative Innovation Centre for Cardiovascular Disorders, Beijing, China
‡The Key Laboratory of Remodelling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing 100029, China
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Jun Guo;
Jun Guo
*Beijing Anzhen Hospital, Capital Medical University, Beijing, China
†Beijing Collaborative Innovation Centre for Cardiovascular Disorders, Beijing, China
‡The Key Laboratory of Remodelling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing 100029, China
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Lixin Jia;
Lixin Jia
*Beijing Anzhen Hospital, Capital Medical University, Beijing, China
†Beijing Collaborative Innovation Centre for Cardiovascular Disorders, Beijing, China
‡The Key Laboratory of Remodelling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing 100029, China
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Toshio Nakanishi;
Toshio Nakanishi
¶Department of Paediatric Cardiology, the Heart Institute, Tokyo Women's Medical University, Tokyo, Japan
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Tao Cai;
Tao Cai
*Beijing Anzhen Hospital, Capital Medical University, Beijing, China
†Beijing Collaborative Innovation Centre for Cardiovascular Disorders, Beijing, China
‡The Key Laboratory of Remodelling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing 100029, China
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Hong Gu;
§Department of Paediatric Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
Correspondence: Dr Hong Gu (email [email protected]) or Dr Jie Du (email [email protected]).
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Jie Du
*Beijing Anzhen Hospital, Capital Medical University, Beijing, China
†Beijing Collaborative Innovation Centre for Cardiovascular Disorders, Beijing, China
‡The Key Laboratory of Remodelling-Related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing 100029, China
Correspondence: Dr Hong Gu (email [email protected]) or Dr Jie Du (email [email protected]).
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Publisher: Portland Press Ltd
Received:
March 31 2016
Revision Received:
June 10 2016
Accepted:
June 17 2016
Accepted Manuscript online:
June 17 2016
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2016
Clin Sci (Lond) (2016) 130 (17): 1559–1569.
Article history
Received:
March 31 2016
Revision Received:
June 10 2016
Accepted:
June 17 2016
Accepted Manuscript online:
June 17 2016
Citation
Chunmei Piao, Yan Zhu, Chen Zhang, Xin Xi, Xuxia Liu, Shuai Zheng, Xiaoyan Li, Jun Guo, Lixin Jia, Toshio Nakanishi, Tao Cai, Hong Gu, Jie Du; Identification of multiple ACVRL1 mutations in patients with pulmonary arterial hypertension by targeted exome capture. Clin Sci (Lond) 1 September 2016; 130 (17): 1559–1569. doi: https://doi.org/10.1042/CS20160247
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