Heterozygous germline mutations in BMPR2, encoding a TGF-β receptor, cause familial primary pulmonary hypertension

Primary pulmonary hypertension (PPH), characterized by obstruction of pre-capillary pulmonary arteries, leads to sustained elevation of pulmonary arterial pressure (mean >25 mm Hg at rest or >30 mm Hg during exercise1). The aetiology is unknown, but the histological features reveal proliferation of endothelial and smooth muscle cells with vascular remodelling2 (Fig. 1). More than one affected relative has been identified in at least 6% of cases3 (familial PPH, MIM 178600). Familial PPH (FPPH) segregates as an autosomal dominant disorder with reduced penetrance and has been mapped to a locus designated PPH1 on 2q33, with no evidence of heterogeneity4,5,6. We now show that FPPH is caused by mutations in BMPR2, encoding a TGF-β type II receptor (BMPR-II). Members of the TGF-β superfamily transduce signals by binding to heteromeric complexes of type I and II receptors, which activates serine/threonine kinases, leading to transcriptional regulation by phosphorylated Smads7. By comparison with in vitro studies, identified defects of BMPR-II in FPPH are predicted to disrupt ligand binding, kinase activity and heteromeric dimer formation8,9,10. Our data demonstrate the molecular basis of FPPH and underscore the importance in vivo of the TGF-β signalling pathway in the maintenance of blood vessel integrity.Figure 1Clinical and histological features of FPPH.a, Chest radiograph showing increase in size of the cardiac silhouette due to right atrial and ventricular dilatation, central pulmonary artery dilatation and attenuation of the pulmonary arterial vascular markings. b, Photomicrograph of a surgical lung biopsy from an individual with PPH, demonstrating occlusion of a pre-capillary pulmonary artery with severe concentric proliferation of the vascular intima and moderate hypertrophy of the media. Normal alveoli surround the vessel with a normal airway below.[graphic not available: see fulltext]