Penetrance of Pulmonary Arterial Hypertension Is Modulated by the Expression of Normal BMPR2 Allele

Hum Mutat. 2009 Apr;30(4):649-54. doi: 10.1002/humu.20922.


Familial pulmonary arterial hypertension (FPAH) is a progressive, fatal disease caused by mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2). FPAH is inherited as an autosomal dominant trait, and shows incomplete penetrance in that many with BMPR2 mutations do not develop FPAH, suggesting a role for, as yet unidentified, modifier genes in disease penetrance. We hypothesized that variable levels of expression of the wild-type (WT) BMPR2 allele could act as a modifier and influence penetrance of FPAH. WT BMPR2 levels were determined by real-time PCR analysis in lymphoblastoid (LB) cell lines derived from normal controls and individuals with FPAH. The FPAH kindreds analyzed carried mutations that result in the activation of nonsense-mediated decay (NMD) pathway, which leads to the degradation of the mutant RNA, thus ensuring that only the WT BMPR2 transcripts will be detected in the real-time assay. Our data show that WT and mutant BMPR2 levels can be reproducibly measured in patient-derived LB cell lines, and that unaffected mutation carrier-derived LB cell lines have higher levels of WT BMPR2 transcripts than FPAH patient-derived LB cell lines (p<or=0.005). Our findings suggest that the levels of expression of WT BMPR2 allele transcripts is important in the pathogenesis of FPAH caused by NMD(+) mutations. Furthermore, our study illustrates a novel application of lymphoblastoid cell lines in the study of PAH, especially important because the affected site, that is, the lung, is not available for unaffected mutation carriers.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Blotting, Western
  • Bone Morphogenetic Protein Receptors, Type II / genetics*
  • Bone Morphogenetic Protein Receptors, Type II / metabolism
  • Cell Line, Transformed
  • Family Health
  • Gene Expression*
  • Genotype
  • Humans
  • Hypertension, Pulmonary / blood
  • Hypertension, Pulmonary / genetics*
  • Hypertension, Pulmonary / pathology
  • Mutation
  • Penetrance
  • Reverse Transcriptase Polymerase Chain Reaction


  • BMPR2 protein, human
  • Bone Morphogenetic Protein Receptors, Type II