Mutations of the TGF-β type II receptorBMPR2 in pulmonary arterial hypertension

Abstract

Communicated by Maria Rita Passos-BuenoPulmonary arterial hypertension (PAH) is clinically characterized by a sustained elevation in mean pulmonary artery pressure leading to significant morbidity and mortality. The disorder is typically sporadic, and in such cases the term idiopathic PAH (IPAH) is used. However, cases that occur within families (familial PAH (FPAH)) display similar clinical and histopathological features, suggesting a common etiology. Heterozygous mutations of a type II member of the TGF-b cell signaling superfamily known as BMPR2 on chromosome 2q33 have been identified in many kindreds with FPAH, yet display both reduced penetrance and sex bias. 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. This large data set characterizes the extent of sequence variation and reveals that the majority (71%) of mutations in FPAH and IPAH comprise nonsense, frameshift, and splice-site defects, and gene rearrangements. These predict premature termination of the transcript with likely loss through the process of nonsense-mediated decay (NMD). A total of 44 missense mutations were identified that substitute amino acid residues at highly conserved sites within recognized functional domains of the mature receptor. We assess this category of mutations in the context of their heterogeneous effects on cell signaling when assayed by in vitro cell-based systems. Disease-causing mutation hot-spots within BMPR2 are summarized. Taken together, these observations are likely to aid in the development of targeted mutation detection strategies relevant for patient management. Finally, we examine the age-and sex-dependent reduced penetrance of BMPR2 mutations by reviewing bmpr2 animal models and the requirement for additional genetic and/or environmental modifiers of disease. In conclusion, these data provide compelling genetic evidence that haploinsufficiency is the predominant molecular mechanism underlying disease predisposition, and support the

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

“…More than 140 distinct mutations of BMPR2 gene have been identified in patients with PAH from a wide range of ethnic groups. 8 In this study, we identified three novel exonic mutations of the BMPR2 gene in the Chinese PAH patients (Table 2), including a frame shift mutation in exon 5 (Leu203fsX15), a nonsense mutation in exon 3 (Glu98X) and a missense mutation in exon 12 (Ser863Asn). These disease-causing mutations are predicted to affect different domains of the BMPR2 protein and mutations within different regions may vary in their impact on disease initiation and progression.…”

Guidelines for the diagnosis and treatment of pulmonary hypertension

“…Heritable forms of PAH include clinically sporadic idiopathic PAH (IPAH) with germline mutations (mainly of the bone morphogenetic protein receptor 2 gene as well as the activin receptor-like kinase type-1 gene or the endoglin gene) and clinical familial cases with or without identified germline mutations [14,15]. This new category of heritable PAH does not mandate genetic testing in any patient with IPAH or in familial cases of PAH because this would not change the clinical management.…”

TGF-β signaling in vascular biology and dysfunction

“…Heterozygous germ line mutations in the BMP receptor II gene (BMPRII) have been found in more than 80% of familial PAH patients. In addition, about 20% of patients with idiopathic PAH were reported to have mutations in BMPRII [99,100]. A recent study has implicated mutations of ALK1 in children with PAH [101].…”