We conducted a molecular study of BMPR2 mutations in 4 Japanese families with familial PPH and 30 Japanese patients with sporadic PPH, and found 13 different mutations, of which 10 were novel, including missense (n=2), nonsense (n=4), frameshift (n=3), and splice-donor site (n=1) mutations.
The first case of BMPR2 mutation found in Japan is reported here in a 19-year-old woman with a clinical diagnosis of PPH and no identifiable family history of pulmonary hypertension.
The findings provide strong evidence that amfepramone can trigger primary pulmonary hypertension in a bone morphogenetic protein receptor type II gene mutation carrier, and indicate that other genes are probably implicated in genetic susceptibility to appetite suppressants.
This study identifies the first function of the BMPR-II tail domain and suggests that the deregulation of actin dynamics may contribute to the etiology of PPH.
Recently, mutations in BMPR2 and ALK-1, genes that encode members of the transforming growth factor-beta (TGF-beta) receptor superfamily, have been found in patients with primary pulmonary hypertension.
To determine whether mutations in the bone morphogenetic protein receptor 2 gene (BMPR2), initially reported in primary pulmonary hypertension, were present in patients with pulmonary arterial hypertension and scleroderma spectrum of disease.Methods.
The differences in biological activities among the BMPR-II mutants observed thus suggest that additional genetic and/or environmental factors may play critical roles in the pathogenesis of PPH.
The failure to find BMPR2 mutations in all families with familial PPH and in all patients with sporadic PPH suggests that other genes remain to be identified.
Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene, the activin receptor-like kinase 1 (ALK1) gene, and SMAD8 gene have been reported in heritable pulmonary arterial hypertension (HPAH) and in idiopathic pulmonary arterial hypertension (IPAH).
Five additional heterozygous missense variants in KCNK3 were independently identified in 92 unrelated patients with familial pulmonary arterial hypertension and 230 patients with idiopathic pulmonary arterial hypertension.