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Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein

Z Deng1, J H Morse, S L Slager

  • 1Department of Psychiatry, College of Physicians and Surgeons at Columbia University and the New York State Psychiatric Institute, New York, NY, USA.

American Journal of Human Genetics
|July 25, 2000
PubMed

Insights

Familial primary pulmonary hypertension (PPH) is linked to chromosome 2q33. Mutations in the BMPR2 gene, affecting bone morphogenetic protein signaling, are identified as a cause of this rare disorder.

Area of Science:

  • Genetics
  • Cardiovascular Medicine
  • Molecular Biology

Background:

  • Familial primary pulmonary hypertension (PPH) is a rare autosomal dominant disorder.
  • PPH is characterized by proliferating endothelial cells in pulmonary arterioles, leading to elevated pulmonary-artery pressures and right-ventricular failure.
  • Secondary pulmonary hypertension can be caused by factors like appetite-suppressant drugs.

Purpose of the Study:

  • To identify the genetic locus and causative gene for familial primary pulmonary hypertension.
  • To investigate the role of bone morphogenetic protein receptor type II (BMPR2) in PPH pathogenesis.

Main Methods:

  • Genotyping of 35 multiplex families using 27 microsatellite markers.
  • Haplotype analysis using the TRANSMIT program to identify shared regions.
  • Sequencing of candidate genes, including BMPR2, using denaturing high-performance liquid chromatography.

Main Results:

  • Suggestive evidence of haplotype sharing at markers GGAA19e07 and D2S307.
  • Five mutations predicting premature protein termination and two missense mutations were identified in the BMPR2 gene in affected individuals.
  • No BMPR2 mutations were found in 196 control chromosomes.

Conclusions:

  • Mutations in the BMPR2 gene are a cause of familial primary pulmonary hypertension.
  • Defects in the bone morphogenetic protein-signaling pathway are implicated in PPH.
  • The findings suggest BMPR2 may also play a role in nonfamilial forms of pulmonary hypertension.

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