Rizwan Hamid
Faculty Member
Last active: 5/30/2014

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

Flynn C, Zheng S, Yan L, Hedges L, Womack B, Fessel J, Cogan J, Austin E, Loyd J, West J, Zhao Z, Hamid R
Am J Respir Cell Mol Biol. 2012 47 (1): 20-7

PMID: 22312021 · PMCID: PMC3402799 · DOI:10.1165/rcmb.2011-0251OC

The molecular mechanisms underlying the reduced penetrance seen in the nonsense-mediated decay-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.

MeSH Terms (16)

Aged Bone Morphogenetic Protein Receptors, Type II Cell Cycle Familial Primary Pulmonary Hypertension Female Gene Expression Profiling Gene Expression Regulation Humans Hypertension, Pulmonary Lung Lymphocytes Male Mutation Penetrance Reactive Oxygen Species Signal Transduction

Connections (6)

This publication is referenced by other Labnodes entities: