Connectivity map analysis of nonsense-mediated decay-positive BMPR2-related hereditary pulmonary arterial hypertension provides insights into disease penetrance.
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.
Departments of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Charles
C
Flynn
Siyuan
S
Zheng
Ling
L
Yan
Lora
L
Hedges
Bethany
B
Womack
Josh
J
Fessel
Joy
J
Cogan
Eric
E
Austin
James
J
Loyd
James
J
West
Zhongming
Z
Zhao
Rizwan
R
Hamid
D000368:Aged; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics* / Q000378:metabolism*; D002453:Cell Cycle; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D009154:Mutation; D019683:Penetrance; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
D017382:Reactive Oxygen Species; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II