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

Nat Genet. 2000 Sep;26(1):81-4. doi: 10.1038/79226.


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-beta type II receptor (BMPR-II). Members of the TGF-beta 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-beta signalling pathway in the maintenance of blood vessel integrity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Bone Morphogenetic Protein Receptors, Type II
  • Chromosomes, Human, Pair 2 / genetics
  • Cloning, Molecular
  • DNA, Complementary / metabolism
  • Endothelium, Vascular / metabolism
  • Exons
  • Family Health
  • Female
  • Genes, Dominant
  • Genetic Linkage
  • Genetic Markers
  • Germ-Line Mutation*
  • Humans
  • Hypertension, Pulmonary / diagnostic imaging
  • Hypertension, Pulmonary / genetics*
  • Hypertension, Pulmonary / metabolism*
  • Introns
  • Ligands
  • Lung / blood supply
  • Lung / diagnostic imaging
  • Male
  • Molecular Sequence Data
  • Muscle, Smooth / metabolism
  • Pedigree
  • Protein Isoforms
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Structure, Tertiary
  • Radiography
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / chemistry
  • Receptors, Transforming Growth Factor beta / genetics
  • Recombination, Genetic
  • Restriction Mapping
  • Sequence Analysis, DNA
  • Sequence Homology, Amino Acid
  • Signal Transduction / genetics


  • DNA, Complementary
  • Genetic Markers
  • Ligands
  • Protein Isoforms
  • Receptors, Transforming Growth Factor beta
  • Protein Serine-Threonine Kinases
  • BMPR2 protein, human
  • Bone Morphogenetic Protein Receptors, Type II
  • Receptor, Transforming Growth Factor-beta Type II