Identification and Functional Analysis of Novel Mutations in AXIN2 and LRP6 Linked With Non-Syndromic Tooth Agenesis.

BACKGROUND: Tooth agenesis (TA) ranks among the most common dental abnormalities. This study aimed to explore the etiology and pathogenesis in Chinese families with non-syndromic TA. METHODS: Chinese families exhibiting non-syndromic TA were recruited. Exome sequencing was conducted to identify mutations in the candidate genes, followed by Sanger sequencing for validation. Functional studies, including bioinformatics analyses, western blots, and dual-luciferase assays, were performed to analyze the impact of the two mutations on the Wnt/β-catenin pathway. RESULTS: We identified a novel heterozygous frameshift insertion in AXIN2 [NM_001363813.1: c.1799dupG (p.Asn601GlnfsTer41)] and a novel de novo heterozygous non-frameshift deletion in LRP6 [NM_002336.3: c.3074_3082del (p.1025_1028del)]. Further functional studies indicated that AXIN2 p.Asn601GlnfsTer41 caused hyperactivation of the Wnt/β-catenin pathway, and LRP6 p.1025_1028del led to pathway suppression. CONCLUSIONS: This study expands the spectrum of AXIN2 and LRP6 mutations associated with non-syndromic TA. Our study provided further functional evidence supporting the pathogenicity of suppression and excessive activation of the Wnt signaling pathway in TA.