J Med Genet 37:741-745 doi:10.1136/jmg.37.10.741
  • Original article

Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-β family

  1. Jennifer R Thomsona,
  2. Rajiv D Machadoa,
  3. Michael W Pauciulob,
  4. Neil V Morgana,
  5. Marc Humbertc,
  6. Greg C Elliottd,
  7. Ken Warde,
  8. Magdi Yacoubf,
  9. Ghada Mikhailf,
  10. Paula Rogersf,
  11. John Newmang,
  12. Lisa Wheelerg,
  13. Timothy Higenbottamh,
  14. J Simon R Gibbsi,
  15. Jim Eganj,
  16. Agnes Crozierk,
  17. Andrew Peacockk,
  18. Robert Allcockl,
  19. Paul Corrisl,
  20. James E Loydg,
  21. Richard C Trembatha,
  22. William C Nicholsb
  1. aDivision of Medical Genetics, Departments of Medicine and Genetics, University of Leicester, UK, bDivision of Human Genetics, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA, cService de Pneumologie et Reanimation Respiratoire, Hopital Antoine Beclere, Clamart, France, dLDS Hospital and the University of Utah, Salt Lake City, Utah 84143, USA, eDepartment of Human Genetics and the Eccles Institute of Human Genetics, University of Utah, Salt Lake City, Utah 84132, USA, fNational Heart & Lung Institute, Royal Brompton & Harefield Hospitals, Harefield, Middlesex, UK, gVanderbilt University Medical Center, Nashville, Tennessee 37232, USA, hDepartment of Respiratory Medicine, Royal Hallamshire Hospital, Sheffield, UK, iNational Heart & Lung Institute, Imperial College of Science, Technology & Medicine, Department of Cardiology, Charing Cross Hospital, London, UK, jDepartment of Respiratory Medicine, Wythenshawe Hospital, Manchester, UK, kScottish Pulmonary Vascular Unit, Western General Hospital, Glasgow, UK, lWilliam Leech Centre for Lung Research, Royal Freeman Hospital, Newcastle upon Tyne, UK
  1. Professor Trembath, rtrembat{at}
  • Revised 21 July 2000
  • Accepted 28 July 2000


BACKGROUND Primary pulmonary hypertension (PPH), resulting from occlusion of small pulmonary arteries, is a devastating condition. Mutations of the bone morphogenetic protein receptor type II gene (BMPR2), a component of the transforming growth factor beta (TGF-β) family which plays a key role in cell growth, have recently been identified as causing familial PPH. We have searched for BMPR2 gene mutations in sporadic PPH patients to determine whether the same genetic defect underlies the more common form of the disorder.

METHODS We investigated 50 unrelated patients, with a clinical diagnosis of PPH and no identifiable family history of pulmonary hypertension, by direct sequencing of the entire coding region and intron/exon boundaries of the BMPR2 gene. DNA from available parent pairs (n=5) was used to assess the occurrence of spontaneous (de novo) mutations contributing to sporadic PPH.

RESULTS We found a total of 11 different heterozygous germline mutations of theBMPR2 gene in 13 of the 50 PPH patients studied, including missense (n=3), nonsense (n=3), and frameshift (n=5) mutations each predicted to alter the cell signalling response to specific ligands. Parental analysis showed three occurrences of paternal transmission and two of de novo mutation of theBMPR2 gene in sporadic PPH.

CONCLUSION The sporadic form of PPH is associated with germline mutations of the gene encoding the receptor protein BMPR-II in at least 26% of cases. A molecular classification of PPH, based upon the presence or absence ofBMPR2 mutations, has important implications for patient management and screening of relatives.