Connectivity map analysis of nonsense-mediated decay-positive BMPR2-related hereditary pulmonary arterial hypertension provides insights into disease penetrance

Charles Flynn, Siyuan Zheng, Ling Yan, Lora Hedges, Bethany Womack, Josh Fessel, Joy Cogan, Eric Austin, James Loyd, James West, Zhongming Zhao, Rizwan Hamid

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

The molecular mechanisms underlying the reduced penetrance seen inthenonsense-mediateddecay-positive(NMD+)BMPR2 mutation-associated hereditary pulmonary arterial hypertension (HPAH) remain unknown. We reasoned that the cellular and genetic mechanisms behind this phenomenon could be uncovered by combining expression profiling with Connectivity Map (cMap) analysis. Cultured lymphocytes from 10 patients with HPAH and 10 matched familial control subjects, all with NMD+ BMPR2 mutations, were subjected to expression analysis. For each group, the expression data were combined before analysis. This generated a signature of 23 up-regulated and 12 down-regulated genes in patients with HPAH compared with control subjects (the "PAH penetrance signature"). Although gene set enrichment analysis of this signature was not uniquely informative, cMap analysis identified drugs with expression signatures similar to the PAH penetrance signature. Several of these drugs were predicted to influence reactive oxygen species (ROS) formation. This hypothesis was tested and confirmed in the same cells initially subjected to the expression analysis using quantitative biochemical detection of ROS concentration. We conclude that expression of the PAH penetrance signature represents an increased risk of developing clinical HPAH and that ROS formation may play a role in pathogenesis of HPAH. These results provide the first molecular insights into NMD+ BMPR2 related HPAH penetrance and highlight the potential utility of cMap analyses in pulmonary research.

Original languageEnglish (US)
Pages (from-to)20-27
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Volume47
Issue number1
DOIs
StatePublished - Jul 2012
Externally publishedYes

Keywords

  • BMPR2
  • Connectivity map
  • Expression signature
  • Hereditary pulmonary arterial hypertention
  • ROS

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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