NEW HOX1A VARIANTS ASSOCIATED WITH BICUSPID AORTIC VALVES
The aortic valve, which regulates the circulation of blood from the heart to the rest of the body, has three leaflets. In some people, however, it has only two leaflets: this is called Bicuspid Aortic Valve (BAV). It is one of the most frequent congenital malformations, affecting more than 1% of the population. While the majority of BAV carriers live normal lives, 30% of these individuals will develop early valve dysfunction. Nevertheless, the embryonic mechanisms involved and the genetic determinants of this pathology remain poorly understood.
A collaborative study led by Dr Stéphane Zaffran involving teams from the University of Aix-Marseille, the IGF in Montpellier (team headed by Chris Jopling), the Catholic University of Louvain and the Thorax Institute in Nantes, has identified mutations in the HOXA1gene in patients with BAV. Using a combination of approaches including zebrafish, mice, in vitro assays and human genetics, this study, published in Nature Communications, showed that the HOXA1 protein plays a role in neural crest cell migration, a process that is essential for the proper formation of aortic leaflets. The mutations identified in patients lead to the production of dominant-negative variants, demonstrating that reduced HOXA1 activity contributes to the BAV phenotype
HOXA1 variants identified in patients with bicuspid aortic valve were tested in vitro and in zebrafish and mouse models to analyze valve shape and neural crest cell migration.
