Computational Analysis of Mutations in WNT10A Gene and Its Structural and Functional Consequences in Tooth Agenesis

The WNT10A gene, which codes for the WNT Family Member 10A (WNT-10a) protein and regulates WNT signaling pathways, has been linked to dental anomaly. WNT-10a protein binds with Frizzled (FZD (FZD1, FZD5 and FZD10) receptors and is involved in tooth development. Mutations in the WNT10A gene cause Oligodontia, tooth agenesis, microdontia and root maldevelopment by impairing WNT signaling. In addition, mutations in the WNT10A gene affect its structure and functional behavior of interaction with FZD receptors. However, the structural changes and interaction behavior of WNT-10 protein upon mutation at the molecular level are still unclear. Hence, in this study, the structural consequences of WNT-10a mutations at the atomic level were elucidated using a molecular simulation approach. Furthermore, docking simulations and MM-GBSA approaches were applied to investigate the interaction pattern of FZD proteins upon mutation in the WNT-10a protein. This study demonstrates that when the WNT-10a protein loses stability, the G213S mutant becomes more flexible, whereas R293C and T357I mutants become more rigid than the wild-type protein. This structural loss affects the interaction between WNT-10a and FZD1, FZD5 and FZD10 receptors which dysregulate the WNT signaling pathway in tooth development. Understanding this mechanism at a molecular level will be beneficial for treating dental anomalies.