Molecular and functional characterization of histidine repeats in HOXA1
(2023)
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- Authors
- Supervisors
- Rezsohazy, René
- Abstract
- The aortic valve is composed of three leaflets and participates in maintaining the unidirectionality of blood flow. The bicuspid aortic valve (BAV) is a cardiac malformation for which the valve is made of two leaflets instead of three (incidence of 0.5% to 2%). It is initially asymptomatic, but the two leaflets will age more rapidly and after fifty or sixty years, BAV can result in stenosis or regurgitation. Eighty-nine percent of BAV cases can be attributed to genetic predisposition. In the previous years, numerous gene mutations have been correlated with BAV in patients, a significant proportion of these genes being known to influence the Wnt signaling pathway. In mice, cells that express the transcription factor HOXA1 participate in the formation of the aortic valve and the knockout of the Hoxa1 gene leads to BAV. In BAV patients, mutations in Hoxa1 that lead to the modification of the length of a histidine track in the protein have been identified. Therefore, this work aims to understand the molecular consequences of the Hoxa1 mutation identified in BAV patients and to gain a better comprehension of the role of histidine repeats. We demonstrated that length modification of the HOXA1 histidine track induces a reduced half-life and a decreased transcriptional activity of the protein. In the mouse, the homologous HOXA1 mutation also leads to BAV. Next, bio-informatic analyses and experimental data support that in proteins that harbor a histidine track, it serves as an interaction surface with cysteine-rich proteins. In HOXA1, the length of the histidine track influences the stability of these interactions, and our data also indicate that they involve the coordination of a metal ion. Finally, considering the involvement of the Wnt pathway in BAV generation, we investigated the possible interaction between this pathway and HOXA1 and revealed an inhibitory effect of HOXA1 onto Wnt activity.
- Affiliations
Citations
Marchese, D. (2023). Molecular and functional characterization of histidine repeats in HOXA1. https://hdl.handle.net/2078.5/99986