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 Scouarnec, Raphaël Chiarelli, Younes Achouri, Emilie Faure, Marine Herbane, Alexis Théron, Jean-François Avierinos, Chris Jopling, Gwenaëlle Collod-Béroud, René Rezsohazy and Stéphane Zaffran ()
Additional contact information
Gaëlle Odelin: Aix Marseille Univ, INSERM, MMG, U1251
Adèle Faucherre: University of Montpellier, CNRS, INSERM
Damien Marchese: Université catholique de Louvain
Amélie Pinard: Aix Marseille Univ, INSERM, MMG, U1251
Hager Jaouadi: Aix Marseille Univ, INSERM, MMG, U1251
Solena Scouarnec: l’institut du thorax, INSERM, CNRS, UNIV Nantes
Raphaël Chiarelli: Université catholique de Louvain
Younes Achouri: de Duve Institute, Université Catholique de Louvain
Emilie Faure: Aix Marseille Univ, INSERM, MMG, U1251
Marine Herbane: Aix Marseille Univ, INSERM, MMG, U1251
Alexis Théron: Aix Marseille Univ, INSERM, MMG, U1251
Jean-François Avierinos: Aix Marseille Univ, INSERM, MMG, U1251
Chris Jopling: University of Montpellier, CNRS, INSERM
Gwenaëlle Collod-Béroud: Aix Marseille Univ, INSERM, MMG, U1251
René Rezsohazy: Université catholique de Louvain
Stéphane Zaffran: Aix Marseille Univ, INSERM, MMG, U1251

Nature Communications, 2023, vol. 14, issue 1, 1-17

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.

Date: 2023
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DOI: 10.1038/s41467-023-37110-x

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