TY - JOUR
T1 - Functional mutations in 5′UTR of the BMPR2 gene identified in Chinese families with pulmonary arterial hypertension
AU - Wang, Jian
AU - Zhang, Chenting
AU - Liu, Chunli
AU - Wang, Wei
AU - Zhang, Nuofu
AU - Hadadi, Cyrus
AU - Huang, Junyi
AU - Zhong, Nanshan
AU - Lu, Wenju
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China grants (81173112, 81470246, 81170052, 81220108001, 81520108001), the Guangzhou Department of Education Yangcheng Scholarship (12A001S), the Guangzhou Department of Natural Science (2014Y2-00167), and the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2014, W Lu), China.
Publisher Copyright:
© 2016 by the Pulmonary Vascular Research Institute. All rights reserved.
PY - 2016/3
Y1 - 2016/3
N2 - Pulmonary arterial hypertension (PAH) is a progressive pulmonary vasculopathy with significant morbidity and mortality. Bone morphogenetic protein receptor type 2 (BMPR2) has been well recognized as the principal gene responsible for heritable and sporadic PAH. Four unrelated Chinese patients with PAH and their family members, both symptomatic and asymptomatic, were genetically evaluated by sequencing all exons and the flanking regions of BMPR2. Functionality of the aberrant mutations at the 5′ untranslated region (UTR) of BMPR2 in the families with PAH was determined by site mutation, transient transfection, and promoter-reporter assays. Four individual mutations in the BMPR2 gene were identified in the 4 families, respectively: 10-GGC repeats, 13-GGC repeats, 4-AGC repeats in 5′UTR, and a novel missense mutation in exon 7 (c.961C>T; p.Arg321X). Moreover, we demonstrated that (1) these 5′UTR mutations decreased the transcription of BMPR2 and (2) the GGC repeats and AGC repeats in BMPR2 5′UTR bore functional binding sites of EGR-1 and MYF5, respectively. This is the first report demonstrating the presence of functional BMPR2 5′UTR mutations in familial patients with PAH and further indicating that EGR-1 and MYF5 are potential targets for correcting these genetic abnormalities for PAH therapy.
AB - Pulmonary arterial hypertension (PAH) is a progressive pulmonary vasculopathy with significant morbidity and mortality. Bone morphogenetic protein receptor type 2 (BMPR2) has been well recognized as the principal gene responsible for heritable and sporadic PAH. Four unrelated Chinese patients with PAH and their family members, both symptomatic and asymptomatic, were genetically evaluated by sequencing all exons and the flanking regions of BMPR2. Functionality of the aberrant mutations at the 5′ untranslated region (UTR) of BMPR2 in the families with PAH was determined by site mutation, transient transfection, and promoter-reporter assays. Four individual mutations in the BMPR2 gene were identified in the 4 families, respectively: 10-GGC repeats, 13-GGC repeats, 4-AGC repeats in 5′UTR, and a novel missense mutation in exon 7 (c.961C>T; p.Arg321X). Moreover, we demonstrated that (1) these 5′UTR mutations decreased the transcription of BMPR2 and (2) the GGC repeats and AGC repeats in BMPR2 5′UTR bore functional binding sites of EGR-1 and MYF5, respectively. This is the first report demonstrating the presence of functional BMPR2 5′UTR mutations in familial patients with PAH and further indicating that EGR-1 and MYF5 are potential targets for correcting these genetic abnormalities for PAH therapy.
KW - Bone morphogenetic protein type 2
KW - Mutation
KW - Pulmonary hypertension
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U2 - 10.1086/685078
DO - 10.1086/685078
M3 - Article
C2 - 27162618
AN - SCOPUS:84977536367
VL - 6
SP - 103
EP - 108
JO - Pulmonary Circulation
JF - Pulmonary Circulation
SN - 2045-8932
IS - 1
ER -