These results support the hypothesis that loss-of-function mutations in BMPR2 could lead to increased pulmonary EC apoptosis, representing a possible initiating mechanism in the pathogenesis of pulmonary arterial hypertension.
This report presents the compilation of data for 144 distinct mutations that alter the coding sequence of the BMPR2 gene identified in 210 independent PAH subjects.
However, despite the fact that most PAH families are consistent with linkage to the BMPR2 locus, sequencing only identifies mutations in some 55% of familial cases and between 10% and 40% of cases without a family history (idiopathic or IPAH).
Defects within bone morphogenetic protein receptor type II gene (BMPR2), coding for a type II receptor member of the transforming growth factor beta (TGF-beta) family, have been shown to underlie familial PAH.
Our findings, taken in context with the observed prevalence of pulmonary arterial hypertension associated with BMPR2 mutations, define converging molecular pathways that lead to the development of pulmonary hypertension, through either genetic or epigenetic loss of function of components of the BMP signaling pathway.
However, less than one-half of BMPR2 mutation carriers develop PAH, suggesting that the most important function of BMPR2 mutation is to cause susceptibility to a "second hit."
Although BMPR2-related pathways seem to be pivotal, many other mediator pathways participate in the pathogenesis of different forms of PAH and are being actively investigated, both independently and in combination.
These results, along with recent reports demonstrating the trapping of PAH-associated human BMPR2 mutants in the Golgi, highlight the implications of disrupted intracellular membrane trafficking in the pathobiology of PAH.
Heterozygous mutations in BMPR2, encoding the type II bone morphogenetic protein receptor (BMPRII), were identified in PAH, suggesting that alterations to BMPRII function are involved in disease onset and/or progression.
We performed genetic testing of the bone morphogenic protein receptor 2 (BMPR2) gene, which mutated in 70% of patients with familial PAH and approximately 25% of patients with idiopathic PAH.
These results demonstrate that the 5'-untranslated region of BMPR2 is considerably longer than previously thought, emphasizing the need to fully characterize the BMPR2 promoter and the importance of analyzing noncoding regions in patients with pulmonary arterial hypertension who are negative for mutations within the coding region and intron-exon junctions.
Not all family members with BMPR2 mutations develop pulmonary arterial hypertension (PAH), implying that additional modifier genes or proteins are necessary for full expression of the disease.
Although patients with PAH and their at-risk relatives typically feel relatively uninformed about testing for mutations in BMPR2 and at times are confused about their testing status, they nonetheless report that it is easy to decide about testing.
It adds further weight to a common molecular pathogenesis in PAH and HHT, and highlights that BMPR2 gene analysis is indicated in patients affected with both HHT and PAH.
Since both the BMPR2 and ALK1 belonging to the transforming growth factor (TGF)-beta superfamily are known to predispose to PAH, mutations in other genes of the TGF-beta/BMP signalling pathways may also predispose to PAH.
We tested the hypothesis that relatives of idiopathic/familial PAH patients display an enhanced frequency of hypertensive TRV response to stress and that this response is associated with mutations in the bone morphogenetic protein receptor II (BMPR2) gene.
Pulmonary arterial hypertension (PAH) has been linked to mutations in genes encoding two members of the transforming growth factor-beta family, BMPR2 and ALK1, the latter of which is also associated with hereditary haemorrhagic telangiectasia (HHT).