Variations in the poly-histidine repeat motif of HOXA1 contribute to bicuspid aortic valve in mouse and zebrafish
Gaëlle Odelin, Adèle Faucherre, Damien Marchese, Amélie Pinard, Hager Jaouadi, Solena Le Scouarnec, Jean‐François Deleuze, Emmanuelle Génin, Pierre Lindenbaum, Richard Redon, Jean‐Jacques Schott, Raphaël Chiarelli, Younès Achouri, Emilie Faure, Marine Herbane, Alexis Théron, Jean-François Aviérinos, Chris Jopling, Gwenaëlle Collod‐Béroud, René Rezsöhazy, Stéphane Zaffran
Abstract
Abstract Bicuspid aortic valve (BAV), the most common cardiovascular malformation occurs in 0.5–1.2% of the population. Although highly heritable, few causal mutations have been identified in BAV patients. Here, we report the targeted sequencing of HOXA1 in a cohort of BAV patients and the identification of rare indel variants in the homopolymeric histidine tract of HOXA1. In vitro analysis shows that disruption of this motif leads to a significant reduction in protein half-life and defective transcriptional activity of HOXA1. In zebrafish, targeting hoxa1a ortholog results in aortic valve defects. In vivo assays indicates that these variants behave as dominant negatives leading abnormal valve development. In mice, deletion of Hoxa1 leads to BAV with a very small, rudimentary non-coronary leaflet. We also show that 17% of homozygous Hoxa1 −1His knock-in mice present similar phenotype. Genetic lineage tracing in Hoxa1 −/− mutant mice reveals an abnormal reduction of neural crest-derived cells in the valve leaflet, which is caused by a failure of early migration of these cells.