Dataset Information

Novel promoter and exon mutations of the BMPR2 gene in Chinese patients with pulmonary arterial hypertension.

ABSTRACT: Pulmonary arterial hypertension (PAH), which is clinically characterized by a sustained elevation in mean pulmonary artery pressure leading to significant morbidity and mortality, is caused by intense remodeling of small pulmonary arteries by endothelial and smooth muscle proliferation. Genetic studies in familial PAH (FPAH) have revealed heterozygous germline mutations in the bone morphogenetic protein type II receptor (BMPR2), a receptor for the transforming growth factor (TGF)-beta/BMP superfamily. In this study, we conducted mutation screening in the promoter region and the entire coding regions as well as the intron/exon boundaries of the BMPR2 gene in 20 Chinese patients with either idiopathic or FPAH. All novel detected mutations were excluded by their presence in a panel of 200 chromosomes from normal individuals. A novel mutation, G-669A, in the promoter sequence of the BMPR2 gene was identified in one patient with FPAH, and no exonic mutations were detected in the proband. This mutation abolished a potential specificity protein 3 (sp3) transcription factor-binding site, and a dual luciferase assay showed that the promoter carrying the -669A allele had significantly decreased transcriptional activity compared with -669G allele. Of the other 19 patients, three novel heterozygous exonic mutations were identified: a frame shift mutation with deletion of TG at the nucleotide position 608-609 in exon 5 (Leu203fsX15), a nonsense mutation at the nucleotide position 292 in exon 3 (Glu98X) and a missense single nucleotide substitution in exon 12 (Ser863Asn).

SUBMITTER: Wang H

PROVIDER: S-EPMC2986562 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Novel promoter and exon mutations of the BMPR2 gene in Chinese patients with pulmonary arterial hypertension.

Wang Hu H Li Wen W Zhang Weili W Sun Kai K Song Xiaodong X Gao Shuo S Zhang Channa C Hui Rutai R Hu Hong H

European journal of human genetics : EJHG 20090218 8

Pulmonary arterial hypertension (PAH), which is clinically characterized by a sustained elevation in mean pulmonary artery pressure leading to significant morbidity and mortality, is caused by intense remodeling of small pulmonary arteries by endothelial and smooth muscle proliferation. Genetic studies in familial PAH (FPAH) have revealed heterozygous germline mutations in the bone morphogenetic protein type II receptor (BMPR2), a receptor for the transforming growth factor (TGF)-beta/BMP superf ...[more]

PMID: 19223935

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Project description:BackgroundMutations in the gene encoding the bone morphogenetic protein receptor type II (BMPR2) are the commonest genetic cause of pulmonary arterial hypertension (PAH). However, the effect of BMPR2 mutations on clinical phenotype and outcomes remains uncertain.MethodsWe analysed individual participant data of 1550 patients with idiopathic, heritable, and anorexigen-associated PAH from eight cohorts that had been systematically tested for BMPR2 mutations. The primary outcome was the composite of death or lung transplantation. All-cause mortality was the secondary outcome. Hazard ratios (HRs) for death or transplantation and all-cause mortality associated with the presence of BMPR2 mutation were calculated using Cox proportional hazards models stratified by cohort.FindingsOverall, 448 (29%) of 1550 patients had a BMPR2 mutation. Mutation carriers were younger at diagnosis (mean age 35·4 [SD 14·8] vs 42·0 [17·8] years), had a higher mean pulmonary artery pressure (60·5 [13·8] vs 56·4 [15·3] mm Hg) and pulmonary vascular resistance (16·6 [8·3] vs 12·9 [8·3] Wood units), and lower cardiac index (2·11 [0·69] vs 2·51 [0·92] L/min per m(2); all p<0·0001). Patients with BMPR2 mutations were less likely to respond to acute vasodilator testing (3% [10 of 380] vs 16% [147 of 907]; p<0·0001). Among the 1164 individuals with available survival data, age-adjusted and sex-adjusted HRs comparing BMPR2 mutation carriers with non-carriers were 1·42 (95% CI 1·15-1·75; p=0·0011) for the composite of death or lung transplantation and 1·27 (1·00-1·60; p=0·046) for all-cause mortality. These HRs were attenuated after adjustment for potential mediators including pulmonary vascular resistance, cardiac index, and vasoreactivity. HRs for death or transplantation and all-cause mortality associated with BMPR2 mutation were similar in men and women, but higher in patients with a younger age at diagnosis (p=0·0030 for death or transplantation, p=0·011 for all-cause mortality).InterpretationPatients with PAH and BMPR2 mutations present at a younger age with more severe disease, and are at increased risk of death, and death or transplantation, compared with those without BMPR2 mutations.FundingCambridge NIHR Biomedical Research Centre, Medical Research Council, British Heart Foundation, Assistance Publique-Hôpitaux de Paris, INSERM, Université Paris-Sud, Intermountain Research and Medical Foundation, Vanderbilt University, National Center for Advancing Translational Sciences, National Institutes of Health, National Natural Science Foundation of China, and Beijing Natural Science Foundation.

Dataset Information

Novel promoter and exon mutations of the BMPR2 gene in Chinese patients with pulmonary arterial hypertension.

Publications

Novel promoter and exon mutations of the BMPR2 gene in Chinese patients with pulmonary arterial hypertension.

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