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 exercise 1 ). The aetiology is unknown, but the histological features reveal proliferation of endothelial and smooth muscle cells with vascular remodelling 2 ( Fig. 1 ). More than one affected relative has been identified in at least 6% of cases 3 (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 heterogeneity 4 , 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 Smads 7 . By comparison with in vitro studies, identified defects of BMPR-II in FPPH are predicted to disrupt ligand binding, kinase activity and heteromeric dimer formation 8 , 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 1 Clinical 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. † These authors contributed equally to this work. * Micheala Aldred 2 , Christopher A. Brannon 3 , P. Michael Conneally 4 , Tatiana Foroud 4 , Neale Fretwell 2 , Radhika Gaddipati 1 , Daniel Koller 4 , Emily J. Loyd 1 , Neil Morgan 2 , John H. Newman 1 , Melissa A. Prince 1 , Carles Vilariño Güell 2 & Lisa Wheeler 1 1 Vanderbilt University Medical Center, Nashville, Tennessee, USA. 2 Division of Medical Genetics, Departments of Genetics and Medicine, University of Leicester, UK. 3 Division of Human Genetics, Children's Hospital Medical Center, Cincinnati, Ohio, USA. 4 Indiana University School of Medicine, Indianapolis, Indiana, USA. Correspondence should be addressed to J.E.L. (e-mail: Jim.Loyd@mcmail.vanderbilt.edu), W.C.N. (e-mail: bill.nichols@chmcc.org) or R.C.T. (e-mail: rtrembat@hgmp.mrc.ac.uk).