Russ Altman, Doctoral (Program)
Rationale: Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disorder characterized by progressive loss of pulmonary microvessels. While mutations in the bone morphogenetic receptor (BMPR) 2 are found in 80% of heritable and ±15% of IPAH patients, their low penetrance (±20%) suggests that other as-yet unidentified genetic modifiers are required for manifestation of the disease phenotype. Use of whole exome sequencing (WES) has recently led to the discovery of novel susceptibility genes in heritable PAH but whether WES can also accelerate gene discovery in IPAH remains unknown. Objectives: To determine whether WES can help identify novel gene modifiers in IPAH patients. Methods and Measurements: Exome capture and sequencing was performed on genomic DNA isolated from 12 unrelated IPAH patients lacking BMPR2 mutations. Observed genetic variants were prioritized according to their pathogenic potential using ANNOVAR. Main Results: A total of 10 genes were identified as high priority candidates. Our top hit was TopBP1, a gene involved in the response to DNA damage and replication stress. We found that TopBP1 expression was reduced in vascular lesions and pulmonary endothelial cells isolated from IPAH patients. While TopBP1 deficiency made endothelial cells susceptible to DNA damage and apoptosis in response to hydroxyurea, its restoration resulted in less DNA damage and improved cell survival. Conclusions: WES led to the discovery of TopBP1, a gene whose deficiency may increase susceptibly to small vessel loss in IPAH. We predict that use of WES will help identify gene modifiers that influence an individual's risk of developing IPAH.
View details for DOI 10.1164/rccm.201310-17490C
View details for Web of Science ID 000336017200018