BMPR2 Haploinsufficiency as the Inherited Molecular Mechanism for Primary Pulmonary Hypertension

Abstract

Primary pulmonary hypertension (PPH) is a potentially lethal disorder, because the elevation of the pulmonary arterial pressure may result in right-heart failure. Histologically, the disorder is characterized by proliferation of pulmonary-artery smooth muscle and endothelial cells, by intimal hyperplasia, 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 b (TGF-b) cell-signaling superfamily, have been identified in familial and sporadic cases of PPH. We report the molecular spectrum of BMPR2 mutations in 47 additional families with PPH and in three patients with sporadic PPH. Among the cohort of patients, we have identified 22 novel mutations, including 4 partial deletions, distributed throughout the BMPR2 gene. The majority (58%) of mutations are predicted to lead to a premature termination codon. We have also investigated the functional 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 the identified mutations. These data support the suggestion that haploinsufficiency represents the common molecular mechanism in PPH. Marked variability of the age at onset of disease was observed both within and between families. Taken together, these studies illustrate the considerable heterogeneity of BMPR2 mutations that cause PPH, and they strongly suggest that additional factors, genetic and/or environmental, may be required for the development of the clinical phenotype.

Neonatal Hyperoxia Causes Pulmonary Vascular Disease and Shortens Life Span in Aging Mice

“…This age-dependent loss of BMP signaling may cause or contribute to lung disease because loss of BMP signaling in precapillary arterioles and microvascular endothelial cells via mutations in BMPR-II is associated with heritable forms of pulmonary hypertension. 42,46 Likewise, BMPR-II expression declines in hypoxia and monocrotaline models of pulmonary hypertension. 47,48 Adenoviral-mediated gene delivery of BMPR-II protects against hypoxia-induced pulmonary hypertension.…”

Novel promoter and exon mutations of the BMPR2 gene in Chinese patients with pulmonary arterial hypertension

“…The mature protein harbors four discrete functional domains, including an extracellular ligand-binding domain encoded by exons 1 -3, a transmembrane domain generated by exon 4, a serine/threonine kinase domain from exon 5 -11 and a very large intracellular C-terminal domain of unknown function from exons 12 and 13. 16 This large C-terminal domain is present only in BMPR2 within the TGF-b receptor superfamily. More than 140 distinct mutations of BMPR2 gene have been identified in patients with PAH from a wide range of ethnic groups.…”

Clinical and Molecular Genetic Features of Pulmonary Hypertension in Patients with Hereditary Hemorrhagic Telangiectasia

“…To determine the prevalence of mutations in ALK1 in subjects with primary pulmonary hypertension who had no personal or family history of hereditary hemorrhagic telangiectasia, we also assessed 11 subjects with familial primary pulmonary hypertension and 24 subjects with sporadic primary pulmonary hypertension, in whom the results of analysis for mutations in BMPR2 were negative; the clinical features of these subjects have previously been described. 20,21 …”

“…26 The fragments were amplified by the polymerase chain reaction (PCR) and excess primer was removed from the amplified fragments with the use of a purification kit (QIAquick, Qiagen, Crawley, West Sussex, United Kingdom) and sequenced with a dye-terminator cycle-sequencing system (ABI PRISM 377, Perkin-Elmer Applied Biosystems, Foster City, Calif.). Analysis of BMPR2 sequence (exons 1 through 13) and gene dosage (exons 1 and 12) was performed in each family member with pulmonary hypertension as previously described 10,21 (information on primer sequences is available as Supplementary Appendix 1 with the full text of this article at http:// www.nejm.org).…”

“…The majority of defects in BMPR2 in patients with primary pulmonary hypertension are predicted to generate either a substantially truncated protein or a reduction in the functional activity of the mature protein, a mechanism known as haploinsufficiency. 21 The deletion of the cytosine residue at position 37 in ALK1 is predicted to result in a markedly abbreviated transcript, suggesting that a similar mechanism perturbs the function of activin-receptor-like kinase 1 in inherited pulmonary hypertension associated with hereditary hemorrhagic telangiectasia. No mutations in ALK1 were identified in 35 subjects with isolated primary pulmonary hypertension.…”