A Novel Mutation in BMPR2 in Patients with Congenital Heart Disease and Pulmonary Arterial Hypertension

Abstract

Background: Pulmonary arterial hypertension (PAH) is caused by intensive remodeling of small pulmonary arteries. The main pathological characteristic is proliferation of endothelial and smooth muscle cells. PAH is clinically characterized by a sustained increase in pulmonary arterial pressure, right-sided heart failure and death. Genetic studies in patients of familial PAH (FPAH), idiopathic pulmonary arterial hypertension (IPAH) and congenital heart disease with pulmonary arterial hypertension (CHD/PAH) have identified heterozygous mutations in the bone morphogenetic protein type receptor II ( BMPR2 ) gene. To date, only six distinct missense mutations have been identified in patients with CHD/ PAH. Methods: The protein-coding region and intron/exon boundaries of the BMPR2 gene were amplified by PCR using DNA samples from 80 Chinese Han patients with CHD/PAH and 80 matched controls. Direct sequencing of PCR products was conducted on both the sense and antisense strands. Mutations were excluded if present in a panel of chromosomes from 80 normal individuals. Results: A novel missense mutation, a G-to-A transition at position 1042 in exon 8, which encodes a Val348Ile mutation, of the BMPR2 gene, was identified in a female pediatric patient with atrioventricular septal defect/anterior mitral valve cleft/pulmonary arterial hypertension (AVSD/ AMVC/PAH). A single nucleotide polymorphisms (SNP), c. 2811G>A, in the BMPR2 gene was identified in nine patients and ten controls. However, no significant difference was found in the frequency distribution of the SNP between patients with CHD/PAH and controls. Conclusions: We identified a novel missense mutation occurring at a valine located in the kinase domain of BMPR2 . The Val348Ile mutation may be responsible for the development of CHD/PAH.