Pathogenicity Assessment of a Bicuspid Aortic Valve Associated ELASTIN Variant Using a Zebrafish Model
BERNARD, V. G.; THERON, A.; DROUARD, A.; AVIERINOS, J.-F.; JOPLING, C.; ZAFFRAN, S.; FAUCHERRE, A.
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Bicuspid aortic valve (BAV) is one of the most common congenital heart defects but its genetic basis remains incompletely defined. Extracellular matrix components play key roles in outflow tract (OFT) and valve development, but their contribution to BAV is not fully established. Following the analysis of a cohort of BAV patients, we identified a family harbouring a rare human ELASTIN (ELN) variant (p.Gln691X). To assess its pathogenicity, we generated a zebrafish elna/b double knockout (KO) using an RNAless CRISPR Cas9 strategy to avoid genetic compensation. This mutant exhibited cardiovascular defects including OFT anomalies, reduced stroke volume and dysmorphic aortic valves, highlighting Elastins critical role in cardiac development. We then used this model to test the ELN variant identified in the BAV family. We found that wild-type ELN mRNA was able to restore normal cardiac function and morphology, whereas the variant ELN mRNA failed to do so. This study establishes a robust in vivo model to assess ELN variant pathogenicity and provides evidence linking ELASTIN to BAV, opening new avenues for uncovering the genetic mechanisms underlying BAV.
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