A novel EDAR variant identified in non-syndromic tooth agenesis: Insights from molecular dynamics

Abstract

Objective: This study aims to investigate a novel pathogenic variant in a Chinese family of non-syndromic tooth agenesis (NSTA) and study the impact of the variant on related protein and pathway.

Design: One NSTA family was collected. Whole exome sequencing and Sanger sequencing were performed on the proband with NSTA and his 5 family members. The pathogenic influence of the mutant is evaluated by bioinformatics analyses including evolutionary conservation analysis and secondary structure prediction. Molecular dynamics (MD) simulations and binding free energy calculations were then performed to explore changes in the tertiary structure and binding ability of the protein.

Results: We found a novel missense ectodysplasin A receptor (EDAR) variant (c .1292 T > G; p.Ile431Arg) in all affected family members. The results of bioinformatics analyses revealed that the EDAR had harmful changes after mutation. MD simulations and the binding free energy calculations results showed that the mutant EDAR protein and EDAR/ectodysplasin-A receptor-associated adapter (EDARADD) complex displayed tertiary structural change, and EDAR possessed a lower affinity to EDARADD after mutation.

Conclusions: We found a novel EDAR variant (c.1292 T > G; p.Ile431Arg) in one NSTA family, which affects the binding of EDAR and EDARADD.

Keywords: EDA pathway; EDAR; Missense variant; Molecular dynamics simulations; Tooth agenesis; WES.