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

Circulation
Diana FulmerJoshua H Lipschutz

Abstract

Bicuspid aortic valve (BAV) disease is a congenital defect that affects 0.5% to 1.2% of the population and is associated with comorbidities including ascending aortic dilation and calcific aortic valve stenosis. To date, although 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 comorbidities. We performed genome-wide association Discovery and Replication Studies using cohorts of 2131 patients with BAV and 2728 control patients, respectively, which identified primary cilia genes as associated with the BAV phenotype. Genome-wide association study hits were prioritized based on P value and validated through in vivo loss of function and rescue experiments, 3-dimensional immunohistochemistry, 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 immunohistochemistry analyses, and assessment of aortic valve an...Continue Reading

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Citations

Mar 19, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ali S AlqahtaniAli El-Gamal
May 23, 2020·Journal of Cardiovascular Development and Disease·Neha AhujaDeborah Garrity
Jan 16, 2020·Journal of Cardiovascular Development and Disease·Kelsey MooreRussell A Norris
Sep 26, 2020·Frontiers in Physiology·Borja Antequera-GonzálezJosep M Alegret
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Feb 27, 2021·American Journal of Human Genetics·Theodore George DrivasMarylyn DeRiggi Ritchie
Mar 28, 2021·Pharmacology & Therapeutics·Max Duong PhuMelanie Philipp
Apr 4, 2021·Journal of Cardiovascular Development and Disease·Kelsey MooreRussell A Norris
Apr 4, 2021·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Lilong GuoRussell A Norris
Apr 30, 2021·Circulation Research·Marko T Boskovski, Thomas G Gleason
Apr 30, 2021·Circulation Research·Mark C BlaserElena Aikawa
Apr 30, 2021·Circulation Research·Punashi DuttaJoy Lincoln
Aug 27, 2021·Journal of Cardiovascular Development and Disease·Christine B Kern
Dec 5, 2021·Nature Reviews. Cardiology·Lydia DjenouneShiaulou Yuan
Dec 8, 2021·Journal of the American Heart Association·Jordan E MorningstarRussell A Norris

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