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

Area of Science:

• Genetics
• Developmental Biology
• Oral Health

Background:

• Tooth agenesis (TA) is a common congenital dental anomaly.
• Understanding the genetic basis of non-syndromic TA is crucial for diagnosis and treatment.

Purpose of the Study:

• To investigate the genetic etiology and pathogenesis of non-syndromic tooth agenesis in Chinese families.
• To identify novel mutations in candidate genes and elucidate their functional impact on the Wnt/β-catenin pathway.

Main Methods:

• Recruitment of Chinese families with non-syndromic TA.
• Exome and Sanger sequencing to identify gene mutations.
• Functional studies including bioinformatics, western blots, and dual-luciferase assays to assess Wnt/β-catenin pathway activity.

Main Results:

• Identified a novel heterozygous frameshift insertion in AXIN2 (c.1799dupG) and a de novo heterozygous deletion in LRP6 (c.3074_3082del).
• AXIN2 mutation led to Wnt/β-catenin pathway hyperactivation.
• LRP6 mutation resulted in Wnt/β-catenin pathway suppression.

Conclusions:

• Expands the known spectrum of AXIN2 and LRP6 mutations linked to non-syndromic TA.
• Provides functional evidence for the role of Wnt signaling pathway dysregulation (both suppression and excessive activation) in TA pathogenesis.