Bicuspid Aortic Valve (or BAV) is the most common cardio-vascular malformation. In BAV, the valve between the left ventricle of the heart and the aorta is composed of two leaflets instead of three in the normal conditional. Initially asymptomatic, BAV can lead to severe complications including aortic stenosis, regurgitation, endocarditis or aortic dissection. Genetic studies have established that BAV is a heritable trait, but only a few gene mutations have been associated to BAV in humans. The HOXA1 gene codes for a regulatory protein fulfilling critical functions in the developing embryo. In particular, inactivation of HOXA1 in model organisms was identified to cause heart malformations at the level of its arterial pole. In this study, we sequenced the HOXA1 gene in a large cohort of patients showing BAV and identified potentially pathogenic mutations in about 10% of the patients. These mutations alter a repetition of histidine (His) residues in the HOXA1 protein. We next demonstrated that the altered protein displays a severely decreased activity as well as a severely decreased stability. The mutant form of HOXA1 displays a dominant negative influence towards the wildtype protein, which is consistent with the observation that patients are heterozygous for the mutations. We next reproduced the mutant HOXA1 condition in zebrafish and mouse. Both animal models present valvular defects consistent with the pathogenic condition in humans. Together, our study establishes the association between HOXA1 mutations in patients and the molecular and developmental etiology of BAV. The study results from a fruitful collaboration between Aix-Marseille Université (team of Dr Stéphane Zaffran, corresponding author of the study), and LIBST at UCLouvain. Damien Marchese, UCLouvain research assistant (team of Prof. René Rezsohazy at LIBST), is co-first author on this publication. Collaborations also involved the universities of Montpellier and Nantes and the Transgenesis platform of UCLouvain in Woluwe (Dr Younes Achouri).
“Variations in the poly-histidine repeat motif of HOXA1 contribute to bicuspid aortic valve in mouse and zebrafish”, Nature Communications, 2023-03-20, DOI 10.1038/s41467-023-37110-x
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