Abstract 14231: The Role of Altered Notch-Sox9-Hapln1 Signaling in the Pathogenesis of Bicuspid Aortic Valve

Abstract

Bicuspid aortic valve (BAV) is a common congenital valve disorder with a prevalence close to 1%. Genetic studies on familial forms of BAV had previously identified NOTCH1 receptor as key mediator in the disease pathogenesis. However, the role of different Notch ligands in valve development in health and disease has remained elusive. Here we sequenced a total of 158 individuals with BAV and identified a list of 12 genes significantly enriched in the patients. Among the identified genes, there were various mutations in NOTCH1 receptor and Notch ligands. To further dissect the role of various Notch ligands in valve development, we generated knock-out models of Jag1a, Jag2b, Dll4, and Dld in Zebrafish and explored their effect on the heart outflow tract. Interestingly, Jag1a and Jag2b had opposite effects on valve diameter. Using single cell RNA and bulk RNA seq, and chip sequencing techniques on murine knock-out models of the corresponding genes, we identified a novel Notch-Sox9-Hapln1 signaling pathway dysregulated in the genetic models of Notch mutation that could underlie the changes in endocardial cells. Finally, we observed alterations in this pathway in aortic valve specimens from patients with bicuspid versus tricuspid aortic valves. In conclusion, our study identifies an association between mutations in Notch ligands and BAV and highlights the role of Notch-Sox9-Hapln1 pathway in aortic valve development and implicates its altered function as a novel pathway for the pathogenesis of BAV.