Defects in the Exocyst-Cilia Machinery Cause Bicuspid Aortic Valve Disease and Aortic Stenosis

• DOI: 10.1161/circulationaha.119.038376
• Publication Date: 2019-08-07T09:00:18Z
• Authors: Diana Fulmer; Katelynn Toomer; Lilong Guo; Kelsey Moore; Janiece Glover; Reece Moore; Rebecca Stairley; Glenn Lobo; Xiaofeng Zuo; Yujing Dang; Yanhui Su; Ben Fogelgren; Patrick Gerard; Dongjun Chung; Mahyar Heydarpour; Rupak Mukherjee; Simon C. Body; Russell A. Norris; Joshua H. Lipschutz
• Keywords: Ciliogenesis; Ciliopathy; Genome-wide Association Study; Exocyst; Candidate gene

Bicuspid aortic valve (BAV) disease is a congenital defect that affects 0.5% to 1.2% of the population and associated with comorbidities including ascending dilation calcific stenosis. To date, although few causal genes have been identified, genetic basis for vast majority BAV cases remains unknown, likely pointing complex heterogeneity underlying this phenotype. Identifying pathways versus individual gene variants may provide an avenue uncovering additional causes consequent comorbidities.We performed genome-wide association Discovery Replication Studies using cohorts 2131 patients 2728 control patients, respectively, which identified primary cilia as Genome-wide study hits were prioritized based on P value validated through in vivo loss function rescue experiments, 3-dimensional immunohistochemistry, histology, morphometric analyses during morphogenesis aged animals multiple species. Consequences these perturbations cilia-dependent analyzed by Western immunohistochemistry analyses, assessment cardiac determined echocardiography.Genome-wide revealed between variation human cilia. The most single-nucleotide polymorphisms or near are important regulating ciliogenesis exocyst, shuttling chaperones cargo membrane. Genetic dismantling exocyst resulted impaired ciliogenesis, disrupted ciliogenic signaling spectrum defects zebrafish, BAV, valvular stenosis, calcification murine models.These data support required normal implicate disruption its downstream contributory humans.