Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension

Hum Mutat. 2011 Dec;32(12):1385-9. doi: 10.1002/humu.21605. Epub 2011 Oct 11.


Heterozygous germline mutations of BMPR2 contribute to familial clustering of pulmonary arterial hypertension (PAH). To further explore the genetic basis of PAH in isolated cases, we undertook a candidate gene analysis to identify potentially deleterious variation. Members of the bone morphogenetic protein (BMP) pathway, namely SMAD1, SMAD4, SMAD5, and SMAD9, were screened by direct sequencing for gene defects. Four variants were identified in SMADs 1, 4, and 9 among a cohort of 324 PAH cases, each not detected in a substantial control population. Of three amino acid substitutions identified, two demonstrated reduced signaling activity in vitro. A putative splice site mutation in SMAD4 resulted in moderate transcript loss due to compromised splicing efficiency. These results demonstrate the role of BMPR2 mutation in the pathogenesis of PAH and indicate that variation within the SMAD family represents an infrequent cause of the disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Morphogenetic Protein Receptors, Type II / genetics
  • Cohort Studies
  • Familial Primary Pulmonary Hypertension
  • Female
  • Gene Expression Regulation
  • Humans
  • Hypertension, Pulmonary / genetics*
  • Male
  • Sequence Analysis, DNA
  • Signal Transduction / genetics*
  • Smad1 Protein / genetics
  • Smad8 Protein / genetics


  • SMAD1 protein, human
  • SMAD9 protein, human
  • Smad1 Protein
  • Smad8 Protein
  • BMPR2 protein, human
  • Bone Morphogenetic Protein Receptors, Type II