The Heart Valve Society

Back to 2018 Program


Exocyst Mutations Contribute To Cardiac Valvular Disease Through Impaired Ciliogenesis
Diana B. Fulmer1, Katelynn A. Toomer1, Lilong Guo1, Kelsey S. Moore1, Janiece S. Glover1, Simon C. Body2, Joshua H. Lipschutz1, Russell A. Norris1.
1Medical University of South Carolina, Charleston, SC, USA, 2Brigham and Women's Hospital, Boston, MA, USA.

Objective: Mitral valve prolapse (MVP) and bicuspid aortic valve (BAV) are major health burdens that affect 5-7% of individuals and result in thousands of surgeries each year. Valve pathogenesis remains poorly understood, however, we have compelling evidence that advances our understanding of its causes. Genetic and functional analyses revealed primary cilia as a potential common link underlying both diseases, and we showed that they are spatially and temporally expressed on developing cardiac valves. Primary cilia are small cellular appendages that sense changes in the extracellular environment. Here we present new data, highlighting the importance of an octameric protein trafficking complex, the exocyst, in generating primary cilia during normal valve development. These studies provided an understanding of fundamental mechanisms underlying valve formation and established an etiological basis for valve diseases. Additionally, these studies, which capitalize on human genetic data, will be used as a platform for developing therapies to treat these complex cardiac diseases in the future. Methods: A valve-specific Cre was used to genetically ablate Exoc5, a critical exocyst member. 3D reconstructions of neonatal mitral and aortic valves were created to assess morphology, and immunohistochemical stains quantified proliferation and differentiation. Biochemical experiments identified novel interactions between the exocyst complex and other ciliogenic proteins. Results: Valves from Exoc5 mutant mice phenocopy human MVP and BAV. This included enlarged valve leaflets, fusion of aortic cusps, and impaired ciliogenesis. Additionally, mutation of exoc5 in zebrafish reproduced the morphant phenotype, with defects that included cardiac edema and severe arterial stenosis. Rescue of exoc5 mutants with human EXOC5 mRNA reversed the phenotype. Conclusions: Cardiac valvulogenesis is dependent on normal ciliogenesis, and ciliogenesis in cardiac valves, is dependent on the exocyst. These data show that ciliogenic programs are conserved across species, and may explain the increased incidences of cardiac valve abnormalities associated with other ciliopathies.


Back to 2018 Program