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

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Abstract

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.

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 Aldred2, Christopher A. Brannon3, P. Michael Conneally4, Tatiana Foroud4, Neale Fretwell2, Radhika Gaddipati1, Daniel Koller4, Emily J. Loyd1, Neil Morgan2, John H. Newman1, Melissa A. Prince1, Carles Vilariño Güell2 & Lisa Wheeler1 1Vanderbilt University Medical Center, Nashville, Tennessee, USA. 2Division of Medical Genetics, Departments of Genetics and Medicine, University of Leicester, UK. 3Division of Human Genetics, Children's Hospital Medical Center, Cincinnati, Ohio, USA. 4Indiana 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).

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Figure 2: Physical map of the PPH1 interval at 2q33.
Figure 3: Co-segregation and sequence analysis of mutations of BMPR2.
Figure 4: BMPR2 cDNA structure and location of FPPH mutations.

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Acknowledgements

We thank the patients and families for participation; the Pulmonary Hypertension Association for encouragement and support; clinicians and colleagues who provided patient information, including R. Allcock, P. Corris, K. McNeil, C. Peels, D. Williams and Sir M. Yacoub; S. Shackleton for critical reading of the manuscript; and D. Lloyd for assistance with the figures. This work has financial support from the British Heart Foundation (R.C.T., Project grant), the American Heart Association (K.B.L., 9820010SE) and the National Institutes of Health (W.C.N., HL61997; J.E.L., HL48164, HL61997). J.R.T. is a Medical Research Council (UK) Clinical Training Fellow.

Authors
  1. Kirk B. Lane
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  2. Rajiv D. Machado
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  3. Michael W. Pauciulo
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  4. Jennifer R. Thomson
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  5. John A. Phillips
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  6. James E. Loyd
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  7. William C. Nichols
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  8. Richard C. Trembath
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Lane, K., Machado, R., Pauciulo, M. et al. Heterozygous germline mutations in BMPR2, encoding a TGF-β receptor, cause familial primary pulmonary hypertension. Nat Genet 26, 81–84 (2000). https://doi.org/10.1038/79226

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