title: 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).
authors.affiliation: FuWai Cardiovascular Hospital, Cardiovascular Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Wang
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.forename: Weili
authors.initials: W
authors.lastname: Zhang
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Song
authors.forename: Shuo
authors.initials: S
authors.lastname: Gao
authors.forename: Channa
authors.initials: C
authors.lastname: Zhang
authors.forename: Rutai
authors.initials: R
authors.lastname: Hui
authors.forename: Hong
authors.initials: H
authors.lastname: Hu
mesh_terms: D000328:Adult; D001483:Base Sequence; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D002478:Cells, Cultured; D002681:China; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009154:Mutation / Q000502:physiology; D010375:Pedigree; D011401:Promoter Regions, Genetic; D011651:Pulmonary Artery / Q000503:physiopathology; D055815:Young Adult
chemical_list: C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II