BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension

Primary pulmonary hypertension (PPH) is a potentially lethal disorder, beca use the elevation of the pulmonary arterial pressure may result in right-he art failure. Histologically, the disorder is characterized by proliferation of pulmonary-artery smooth muscle and endothelial cells, by intimal hyperp lasia, and by in situ thrombus formation. Heterozygous mutations within the bone morphogenetic protein type II receptor (BMPR-II) gene (BMPR2), of the transforming growth factor beta (TGF-beta) cell-signaling superfamily, hav e been identified in familial and sporadic cases of PPH. We report the mole cular spectrum of BMPR2 mutations in 47 additional families with PPH and in three patients with sporadic PPH. Among the cohort of patients, we have id entified 22 novel mutations, including 4 partial deletions, distributed thr oughout the BMPR2 gene. The majority (58%) of mutations are predicted to le ad to a premature termination codon. We have also investigated the function al impact and genotype-phenotype relationships, to elucidate the mechanisms contributing to pathogenesis of this important vascular disease. In vitro expression analysis demonstrated loss of BMPR-II function for a number of t he identified mutations. These data support the suggestion that haploinsuff iciency represents the common molecular mechanism in PPH. Marked variabilit y of the age at onset of disease was observed both within and between famil ies. Taken together, these studies illustrate the considerable heterogeneit y of BMPR2 mutations that cause PPH, and they strongly suggest that additio nal factors, genetic and/or environmental, may be required for the developm ent of the clinical phenotype.