Novel Dental Anomaly朼ssociated Mutations in WNT10A Protein Binding Sites

Abstract

Objective: WNT/?-catenin signaling is initiated by binding of a WNT protein to a Frizzled (FZD) receptor and a co-receptor low-density lipoprotein (LDL) receptor-related protein 5 or 6 (LRP5/6). The objective of this study was to find the genetic variants responsible for dental anomalies found in 4 families. Methods: Clinical and radiographic examination and whole exome sequencing were performed on 5 patients affected with dental anomalies and the mutant proteins modeled. Results: Five patients were heterozygous for the WNT10A variants including c.877C>T; p.Arg293Cys c.874A>G; p.Ser292Gly c.1042C>T; p.Arg348Cys and c.1039G>T; p.347GluX. The p.Arg293Cys and p.Ser292Gly mutations are located in the WNT10A N-terminal domain region with binding sites for FZD receptor porcupine WNTLESS and extracellular binding proteins so they are likely to have adverse effects on binding these proteins. The p.Arg348Cys mutation which is located in the binding site of LRP5/6 co-receptors is postulated to result in impaired binding to these co-receptors. The nonsense mutation p.347GluX is predicted to result in the truncation of most of the C-terminal domain which is likely to disrupt the binding of WNT10A to WNTLESS the membrane protein that binds lipid-acylated WNT proteins to carry them from the endoplasmic reticulum to the cell surface and FZD. Conclusions: Four novel mutations in WNT10A were identified in patients with isolated tooth agenesis. The mutations in the N-terminal domain and the interface between the N- and C-terminal domains of WNT10A in our patients are likely to disrupt its binding with FZD LRP5/6 and various other proteins involved in WNT10A processing and transport impair WNT and SHH signaling and subsequently result in tooth agenesis microdontia and root maldevelopment. ? 2022 The Authors