Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

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).

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Rubin, L. ACCP consensus statement: primary pulmonary hypertension. Chest 104, 236–250 ( 1993).

    Article  CAS  Google Scholar 

  2. Gaine, S.P. & Rubin, L.J. Primary pulmonary hypertension. Lancet 352, 719–725 ( 1998).

    Article  CAS  Google Scholar 

  3. Rich, S. et al. Primary pulmonary hypertension: a national prospective study. Ann. Intern. Med. 107, 216–223 (1987).

    Article  CAS  Google Scholar 

  4. Loyd, J.E., Primm, R.K. & Newman, J.H. Familial primary pulmonary hypertension: clinical patterns. Am. Rev. Respir. Dis. 129, 194 –197 (1984).

    CAS  PubMed  Google Scholar 

  5. Nichols, W.C. et al. Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31–32. Nature Genet. 15, 277–280 (1997).

    Article  CAS  Google Scholar 

  6. Morse, J.H. et al. Mapping of familial pulmonary hypertension locus (PPH1 ) to chromosome 2q31–32. Circulation 95, 2603–2606 (1997).

    Article  CAS  Google Scholar 

  7. Massagué, J. & Chen, Y.-G. Controlling TGF-β signalling. Genes Dev. 14, 627– 644 (2000).

    PubMed  Google Scholar 

  8. Wrana, J.L. et al. Two distinct transmembrane serine/threonine kinases from Drosophila melanogaster form an activin receptor complex. Mol. Cell. Biol. 14, 944–950 (1994).

    Article  CAS  Google Scholar 

  9. Carcamo, J., Zentella, A. & Massagué, J. Disruption of transforming growth factor β signalling by a mutation that prevents transphosphorylation within the receptor complex . Mol. Cell. Biol. 15, 1573– 1581 (1995).

    Article  CAS  Google Scholar 

  10. Gilboa, L. et al. Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors . Mol. Biol. Cell. 11, 1023– 1035 (2000).

    Article  CAS  Google Scholar 

  11. Hadano, S. et al. A yeast artificial chromosome-based physical map of the juvenile amyotrophic lateral sclerosis (ALS2) critical region on human chromosome 2q33–q34 . Genomics 55, 106–112 (1999).

    Article  CAS  Google Scholar 

  12. Machado, R.D. et al. A physical and transcript map based upon refinement of the critical interval for PPH1, a gene for familial primary pulmonary hypertension . Genomics (in press).

  13. Kawabata, M., Chytil, A. & Moses, H.L. Cloning of a novel type II serine/threonine kinase receptor through interaction with the type I transforming growth factor-β receptor . J. Biol. Chem. 270, 5625– 5630 (1995).

    Article  CAS  Google Scholar 

  14. Liu, F., Ventura, F., Doody, J. & Massagué, J. Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs. Mol. Cell. Biol. 15, 3479–3486 (1995).

    Article  CAS  Google Scholar 

  15. Rosenzweig, B.L. et al. Cloning and characterization of a human type II receptor for bone morphogenetic proteins. Proc. Natl Acad. Sci. USA 92, 7632–7636 (1995).

    Article  CAS  Google Scholar 

  16. Botney, M.D., Bahadori, L. & Gold, L.I. Vascular remodeling in primary pulmonary hypertension. Potential role for transforming growth factor-β. Am. J. Pathol. 144, 286–295 ( 1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Marchuk, D.A. Genetic abnormalities in hereditary hemorrhagic telangiectasia. Curr. Opin. Hematol. 5, 332–338 (1998).

    Article  CAS  Google Scholar 

  18. Beppu, H., Minowa, O., Miyazono, K. & Kawabata, M. cDNA cloning and genomic organization of the mouse BMP type II receptor. Biochem. Biophys. Res. Commun. 235, 499–504 (1997).

    Article  CAS  Google Scholar 

  19. Wilkie, A.O. The molecular basis of genetic dominance. J. Med. Genet. 31, 89–98 (1994).

    Article  CAS  Google Scholar 

  20. Thomson, J.R. & Trembath, R.C. Primary pulmonary hypertension: the pressure rises for a gene. J. Clin. Pathol. (in press).

  21. Lu, S.L. et al. HNPCC associated with germline mutation in the TGF-β type II receptor gene. Nature Genet. 19, 17– 18 (1998).

    Article  CAS  Google Scholar 

  22. Lee, S.D. et al. Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J. Clin. Invest. 101, 927–934 (1998).

    Article  CAS  Google Scholar 

  23. Shackleton, S. et al. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy . Nature Genet. 24, 153– 156 (2000).

    Article  CAS  Google Scholar 

Download references

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/79226

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing