ZFIN ID: ZDB-PUB-190808-9
Defects in the Exocyst-Cilia Machinery Cause Bicuspid Aortic Valve Disease and Aortic Stenosis
Fulmer, D., Toomer, K., Guo, L., Moore, K., Glover, J., Moore, R., Stairley, R., Lobo, G., Zuo, X., Dang, Y., Su, Y., Fogelgren, B., Gerard, P., Chung, D., Heydarpour, M., Mukherjee, R., Body, S.C., Norris, R.A., Lipschutz, J.H.
Date: 2019
Source: Circulation   140(16): 1331-1341 (Journal)
Registered Authors: Lobo, Glenn, Su, Yanhui
Keywords: cilia, exocyst
MeSH Terms:
  • Animals
  • Aortic Valve/abnormalities*
  • Aortic Valve/metabolism
  • Aortic Valve/pathology
  • Aortic Valve Stenosis/genetics
  • Aortic Valve Stenosis/pathology*
  • Case-Control Studies
  • Cilia/pathology
  • Cilia/physiology*
  • Gene Frequency
  • Genome-Wide Association Study
  • Genotype
  • Heart Defects, Congenital/genetics
  • Heart Defects, Congenital/pathology*
  • Heart Valve Diseases/genetics
  • Heart Valve Diseases/metabolism
  • Heart Valve Diseases/pathology*
  • Humans
  • Mice
  • Mice, Knockout
  • Polymorphism, Single Nucleotide
  • Vesicular Transport Proteins/genetics
  • Vesicular Transport Proteins/metabolism
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed: 31387361 Full text @ Circulation
Bicuspid aortic valve (BAV) disease is a congenital defect that affects 0.5-1.2% of the population and is associated with co-morbidities including ascending aortic dilation and calcific aortic valve stenosis (CAVS). To date, while a few causal genes have been identified, the genetic basis for the vast majority of BAV cases remains unknown, likely pointing to complex genetic heterogeneity underlying this phenotype. Identifying genetic pathways versus individual gene variants may provide an avenue for uncovering additional BAV causes and consequent co-morbidities.
We performed a genome wide association (GWAS) and replication study using cohorts of 2,131 BAV and 2,728 control patients, respectively, which identified primary cilia genes as associated with the BAV phenotype. GWAS hits were prioritized based on p-value and validated through in vivo loss of function and rescue experiments, 3D-immunohistochemistry (IHC), histology and morphometric analyses during aortic valve morphogenesis and in aged animals in multiple species. Consequences of these genetic perturbations on cilia dependent pathways were analyzed by Western and IHC analyses, and assessment of aortic valve and cardiac function were determined by echocardiography.
GWAS revealed an association between BAV and genetic variation in human primary cilia. The most associated SNPs were identified in or near genes that are important in regulating ciliogenesis through the exocyst, a shuttling complex that chaperones cilia cargo to the membrane. Genetic dismantling of the exocyst resulted in impaired ciliogenesis, disrupted ciliogenic signaling and a spectrum of cardiac defects in zebrafish, and aortic valve defects including BAV, valvular stenosis, and valvular calcification in murine models.
These data support the exocyst as required for normal ciliogenesis during aortic valve morphogenesis and implicate disruption of ciliogenesis and its downstream pathways as contributory to BAV and associated co-morbidities in humans.