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Low frequency of BMPR2 mutations in a German cohort of patients with sporadic idiopathic pulmonary arterial hypertension
  1. R Koehler1,*,
  2. E Grünig2,*,
  3. M W Pauciulo3,*,
  4. M M Hoeper4,
  5. H Olschewski5,
  6. H Wilkens6,
  7. M Halank7,
  8. J Winkler8,
  9. R Ewert9,
  10. H Bremer10,
  11. S Kreuscher2,
  12. B Janssen1,
  13. W C Nichols3
  1. 1Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
  2. 2Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany
  3. 3Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
  4. 4Department of Pneumology, University of Hannover, Hannover, Germany
  5. 5Department of Pneumology, University of Giessen, Giessen, Germany
  6. 6Department of Pneumology, University of Homburg, Homburg, Germany
  7. 7Department of Pneumology, University of Dresden, Dresden, Germany
  8. 8Department of Pneumology, University of Leipzig, Leipzig, Germany
  9. 9Department of Pneumology, University of Greifswald, Greifswald, Germany
  10. 10Department of Pneumology, University of Freiburg, Freiburg, Germany
  1. Correspondence to:
 Dr William C Nichols
 Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, 1469 TCHRF, Cincinnati, OH 45229, USA;

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Idiopathic pulmonary arterial hypertension (IPAH; formerly known as primary pulmonary hypertension, PPH) is a rare disorder characterised by pulmonary vascular proliferation and remodelling resulting in loss of patency of the pulmonary arteries. This leads to sustained elevation of pulmonary artery pressures with subsequent progressive right heart failure and often death.1–3 While the majority of cases (>90%) have no known family history of the disease, ∼6% of the cases are known to be familial and are inherited in an autosomal dominant manner with markedly reduced penetrance.4 In previous studies, linkage analysis identified a familial IPAH locus on chromosome 2q33.5,6 Subsequent heterozygous germline mutations in the bone morphogenetic protein receptor, type II (BMPR II) gene (BMPR2) were identified in at least 50% of familial cases.7–9 BMPR-II is a member of the transforming growth factor-β (TGF-β) receptor superfamily signalling pathway, which is critical in both cell differentiation and cell growth mediated through transcriptional regulation.10,11 Interestingly, germline mutations were also identified in 26–40% of sporadic cases.12,13 This study was performed to establish the frequency of BMPR2 mutations in a different population of patients with sporadic IPAH.



Between March 2002 and January 2004, 99 consecutive non-related patients >20 years of age with IPAH and negative family history were evaluated. In all cases, diagnosis of IPAH was made by experienced and specialised cardiologists or pulmonologists according to WHO criteria.1,14 Other causes of pulmonary hypertension such as illicit drug abuse or anorectic drug use were excluded by careful medical history evaluation. Underlying heart and lung diseases (recurrent pulmonary embolism, connective tissue disease, obstructive or restrictive lung disease) and HIV infection were excluded by a cascade of clinical examinations including laboratory tests, arterial blood gas analysis, chest x ray, pulmonary function tests, echocardiography, ventilation perfusion …

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  • * These authors contributed equally to this study.

  • The study was funded by the University of Heidelberg and the National Institutes of Health (HL61997).

  • Conflict of interest: none declared.