• Eric D Austin, Lijiang Ma, Charles LeDuc, Erika Berman Rosenzweig, Alain Borczuk, John A Phillips, Teresa Palomero, Pavel Sumazin, Hyunjae R Kim, Megha H Talati, James West, James E Loyd, and Wendy K Chung.
• Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
• Circ Cardiovasc Genet. 2012 Jun 1; 5 (3): 336-43.

BackgroundHeritable and idiopathic pulmonary arterial hypertension (PAH) are phenotypically identical and associated with mutations in several genes related to transforming growth factor (TGF) beta signaling, including bone morphogenetic protein receptor type 2, activin receptor-like kinase 1, endoglin, and mothers against decapentaplegic 9. Approximately 25% of heritable cases lack identifiable mutations in any of these genes.Methods And ResultsWe used whole exome sequencing to study a 3-generation family with multiple affected family members with PAH, but no identifiable TGF beta mutation. We identified a frameshift mutation in caveolin-1 (CAV1), which encodes a membrane protein of caveolae abundant in the endothelium and other cells of the lung. An independent de novo frameshift mutation was identified in a child with idiopathic PAH. Western blot analysis demonstrated a reduction in caveolin-1 protein, while lung tissue immunostaining studies demonstrated a reduction in normal caveolin-1 density within the endothelial cell layer of small arteries.ConclusionsOur study represents successful elucidation of a dominant Mendelian disorder using whole exome sequencing. Mutations in CAV1 are associated in rare cases with PAH. This may have important implications for pulmonary vascular biology, as well as PAH-directed therapeutic development.

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