Understanding the Low Penetrance of Bone Morphogenetic Protein Receptor 2 Gene Mutations

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary circulation in which thrombosis, inflammation, and unbridled cellular proliferation obliterate the arterial lumen, causing progressive right heart failure and death. The pathogenesis remains enigmatic, and current therapeutic strategies are limited. In 1951, Dresdale1 published the first report of a family in which 3 first-degree relatives had what was then called primary pulmonary hypertension. Subsequently, the initial, prospective National Institutes of Health (NIH)-sponsored North American primary pulmonary hypertension registry included 11 patients who had a relevant family history (6%).2 Several features of the gene transmission were apparent by the 1980s: vertical transmission indicated a single dominant gene, transmission to offspring of either sex argued against X- or Y-linkage, and multiple skip generations highlighted an incomplete penetrance.3 Article see p 1907 The race to identify the causative gene was ultimately won simultaneously by 2 groups working in parallel. Nichols et al4 used a microsatellite marker strategy to identify the locus within families on chromosome 2q32. Then groups at Columbia Presbyterian in New York5 and an International Consortium, including Vanderbilt,6 simultaneously identified mutations in a receptor for the transforming growth factor β family, the bone morphogenetic protein receptor 2 (BMPR-2), as the cause of most cases of what is now classified as heritable pulmonary arterial hypertension (HPAH). BMPR-2 mutations have subsequently been found in between 5% and 25% of patients who have idiopathic PAH without any relevant family history.7 Mutations in other transforming growth factor beta family proteins, activin-like kinase-1 and endoglin, are unusual causes for HPAH.8 Although numerous BMPR-2 mutations have been found, in most cases (≈70%) the mutation leads to a haploinsufficient state in which cellular BMPR-2 levels are reduced by ≈50%,9 usually because the mutated transcript is subject to nonsense-mediated …