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

Kirk B. Lane, Rajiv D. Machado, Michael W. Pauciulo, Jennifer R. Thomson, John A. Phillips, James E. Loyd, William C. Nichols, Richard C. Trembath, Micheala Aldred, Christopher A. Brannon, P. Michael Conneally, Tatiana Foroud, Neale Fretwell, Radhika Gaddipati, Daniel Koller, Emily J. Loyd, Neil Morgan, John H. Newman, Melissa A. Prince, Carles Vilariño GüellLisa Wheeler

Research output: Contribution to journalArticlepeer-review

1090 Scopus citations


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). The aetiology is unknown, but the histological features reveal proliferation of endothelial and smooth muscle cells with vascular remodelling (Fig. 1). More than one affected relative has been identified in at least 6% of cases (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. 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. 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. 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.

Original languageEnglish (US)
Pages (from-to)81-84
Number of pages4
JournalNature genetics
Issue number1
StatePublished - Sep 2000

ASJC Scopus subject areas

  • Genetics

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