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New pathogenic variant of BMPR2 in pulmonary arterial hypertension

Published online by Cambridge University Press:  08 April 2019

Xiaofei Yang ,
Qingyu Kong ,
Cuifen Zhao ,
Zhifeng Cai  and
Minmin Wang
Xiaofei Yang
Affiliation:
Department of Pediatrics, Qilu Hospital, Shandong University, Jinan, China Department of Pediatrics, Yidu Central Hospital of Weifang, Weifang, China
Qingyu Kong
Affiliation:
Department of Pediatrics, Qilu Hospital, Shandong University, Jinan, China
Cuifen Zhao*
Affiliation:
Department of Pediatrics, Qilu Hospital, Shandong University, Jinan, China
Zhifeng Cai
Affiliation:
Department of Pediatrics, Qilu Hospital, Shandong University, Jinan, China
Minmin Wang
Affiliation:
Department of Pediatrics, Qilu Hospital, Shandong University, Jinan, China
*
Author for correspondence: Cuifen Zhao, Department of Pediatrics, Qilu Hospital, Shandong University, No. 107 Wenhuaxi Road, Jinan 250012, Shandong Province, China. Tel: +86-531-82169940; Fax: +86-531-86927544. E-mail: zhaocuifen@sdu.edu.cn
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Abstract

Objectives:

The aim of this study was to evaluate the variant frequency of pulmonary arterial hypertension-related genes and provide theoretical basis for genetic screening of patients with pulmonary arterial hypertension further.

Methods:

Ten genes associated with pulmonary arterial hypertension were sequenced in 7 cases of idiopathic pulmonary arterial hypertension and 34 cases of congenital heart disease (CHD) associated with pulmonary arterial hypertension by next-generation high-throughput sequencing. Function prediction and gene variant amino acid conservation were carried out by bioinformatics software. Family study was performed on the patients with the variant.

Results:

A new bone morphogenetic protein receptor type 2(BMPR2) variant (c.344T>C, p. F115S) was discovered in a girl who was diagnosed with idiopathic pulmonary arterial hypertension. Her second aunt and third aunt carried the same variant and were confirmed as patients with pulmonary arterial hypertension as well. No variants or single nucleotide polymorphisms were found in other pulmonary arterial hypertension-associated genes.

Conclusions:

BMPR2 variant is the most common variant of pulmonary arterial hypertension. Genetic screening of BMPR2 variant and family survey in patients with pulmonary arterial hypertension is suggested for the sake of definite cause and better treatment.

Keywords

Pulmonary arterial hypertensionBMPR2genevariant
Type
Original Article
Information
Cardiology in the Young , Volume 29 , Issue 4 , April 2019 , pp. 462 - 466
Copyright
© Cambridge University Press 2019 

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Footnotes

*

Both authors contributed equally to this work and should be considered co-first authors.

References

Humbert, M, Morrell, NW, Archer, SL, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:13S–24S.CrossRefGoogle ScholarPubMed
Galie, N, Humbert, M, Vachiery, JL, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Rev Esp Cardiol (Engl Ed) 2016;69:177.CrossRefGoogle ScholarPubMed
Federici, C, Drake, KM, Rigelsky, CM, et al. Increased mutagen sensitivity and DNA damage in pulmonary arterial hypertension. Am J Respir Crit Care Med 2015;192:219–228.CrossRefGoogle ScholarPubMed
El, CH, Hassoun, PM. Immune and inflammatory mechanisms in pulmonary arterial hypertension. Prog Cardiovasc Dis 2012;55:218–228.Google Scholar
Rabinovitch, M, Guignabert, C, Humbert, M, Nicolls, MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res 2014;115:165–175.CrossRefGoogle ScholarPubMed
Kopec, G, Waligora, M, Tyrka, A, et al. Low-density lipoprotein cholesterol and survival in pulmonary arterial hypertension. Sci Rep 2017;7:41650.CrossRefGoogle ScholarPubMed
Heresi, GA, Malin, SK, Barnes, JW, Tian, L, Kirwan, JP, Dweik, RA. Abnormal glucose metabolism and high-energy expenditure in idiopathic pulmonary arterial hypertension. Ann Am Thorac Soc 2017;14:190–199.Google ScholarPubMed
Rhodes, CJ, Ghataorhe, P, Wharton, J, et al. Plasma metabolomics implicates modified transfer RNAs and altered bioenergetics in the outcomes of pulmonary arterial hypertension. Circulation 2017;135:460–475.CrossRefGoogle ScholarPubMed
Harvey, LD, Chan, SY. Emerging metabolic therapies in pulmonary arterial hypertension. J Clin Med 2017;6:E43.CrossRefGoogle ScholarPubMed
Zhang, R, Jing, ZC. Energetic metabolic roles in pulmonary arterial hypertension and right ventricular remodeling. Curr Pharm Des 2016;22:4780–4795.CrossRefGoogle ScholarPubMed
Thomson, JR, Machado, RD, Pauciulo, MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet 2000;37:741–745.CrossRefGoogle ScholarPubMed
Cogan, JD, Vnencak-Jones, CL, Phillips, JR, et al. Gross BMPR2 gene rearrangements constitute a new cause for primary pulmonary hypertension. Genet Med 2005;7:169–174.CrossRefGoogle ScholarPubMed
Aldred, MA, Vijayakrishnan, J, James, V, et al. BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mutat 2006;27:212–213.CrossRefGoogle ScholarPubMed
Pfarr, N, Fischer, C, Ehlken, N, et al. Hemodynamic and genetic analysis in children with idiopathic, heritable, and congenital heart disease associated pulmonary arterial hypertension. Respir Res 2013;14:3.CrossRefGoogle ScholarPubMed
Wang, H, Ji, R, Meng, J, et al. Functional changes in pulmonary arterial endothelial cells associated with BMPR2 mutations. PLoS One 2014;9:e106703.CrossRefGoogle ScholarPubMed
Montani, D, Price, LC, Girerd, B, et al. Fatal rupture of pulmonary arteriovenous malformation in hereditary haemorrhagic telangiectasis and severe PAH. Eur Respir Rev 2009;18:42–46.CrossRefGoogle ScholarPubMed
Maloney, JP, Stearman, RS, Bull, TM, et al. Loss-of-function thrombospondin-1 mutations in familial pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2012;302:L541–L554.CrossRefGoogle ScholarPubMed
Nasim, MT, Ogo, T, Ahmed, M, et al. Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension. Hum Mutat 2011;32:1385–1389.CrossRefGoogle ScholarPubMed
Chida, A, Shintani, M, Nakayama, T, et al. Missense mutations of the BMPR1B (ALK6) gene in childhood idiopathic pulmonary arterial hypertension. Circ J 2012;76:1501–1508.CrossRefGoogle ScholarPubMed
Austin, ED, Ma, L, LeDuc, C, et al. Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circ Cardiovasc Genet 2012;5:336–343.CrossRefGoogle ScholarPubMed
Chida, A, Shintani, M, Matsushita, Y, et al. Mutations of NOTCH3 in childhood pulmonary arterial hypertension. Mol Genet Genomic Med 2014;2:229–239.CrossRefGoogle ScholarPubMed
Vattulainen, S, Aho, J, Salmenpera, P, et al. Accurate genetic diagnosis of Finnish pulmonary arterial hypertension patients using oligonucleotide-selective sequencing. Mol Genet Genomic Med 2015;3:354–362.CrossRefGoogle ScholarPubMed
Pousada, G, Baloira, A, Fontan, D, Nunez, M, Valverde, D. Mutational and clinical analysis of the ENG gene in patients with pulmonary arterial hypertension. BMC Genet 2016;17:72.CrossRefGoogle ScholarPubMed
Navas, TP, Tenorio, CJ, Palomino, DJ, et al. An homozygous mutation in KCNK3 is associated with an aggressive form of hereditary pulmonary arterial hypertension. Clin Genet 2017;91:453–457.CrossRefGoogle Scholar
Morrell, NW. Pulmonary hypertension due to BMPR2 mutation: a new paradigm for tissue remodeling? Proc Am Thorac Soc 2006;3:680–686.CrossRefGoogle ScholarPubMed
Yang, X, Long, L, Southwood, M, et al. Dysfunctional SMAD signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ Res 2005;96:1053–1063.CrossRefGoogle ScholarPubMed
Gamou, S, Kataoka, M, Aimi, Y, et al. Genetics in pulmonary arterial hypertension in a large homogeneous Japanese population. Clin Genet 2017;94:70–80.CrossRefGoogle Scholar
Austin, ED, Loyd, JE. The genetics of pulmonary arterial hypertension. Circ Res 2014;115:189–202.CrossRefGoogle ScholarPubMed
Roberts, KE, McElroy, JJ, Wong, WP, et al. BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur Respir J 2004;24:371–374.CrossRefGoogle ScholarPubMed
Tatebe, S, Sugimura, K, Aoki, T, et al. The efficacy of a genetic analysis of the BMPR2 Gene in a patient with severe pulmonary arterial hypertension and an atrial septal defect treated with bilateral lung transplantation. Intern Med 2017;56:3193–3197.CrossRefGoogle Scholar
Hadinnapola, C, Bleda, M, Haimel, M, et al. Phenotypic characterization of EIF2AK4 mutation carriers in a large cohort of patients diagnosed clinically with pulmonary arterial hypertension. Circulation 2017;136:2022–2033.CrossRefGoogle Scholar
Garcia-Rivas, G, Jerjes-Sanchez, C, Rodriguez, D, Garcia-Pelaez, J, Trevino, V. A systematic review of genetic mutations in pulmonary arterial hypertension. BMC Med Genet 2017;18:82.CrossRefGoogle ScholarPubMed
Jacher, JE, Martin, LJ, Chung, WK, Loyd, JE, Nichols, WC. Pulmonary arterial hypertension: specialists’ knowledge, practices, and attitudes of genetic counseling and genetic testing in the USA. Pulm Circ 2017;7:372–383.CrossRefGoogle ScholarPubMed