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Functional analysis of a novel missense mutation in AXIN 2 associated with non‐syndromic tooth agenesis
Author(s) -
Yue Haitang,
Liang Jia,
Yang Kai,
Hua Bo,
Bian Zhuan
Publication year - 2016
Publication title -
european journal of oral sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.802
H-Index - 93
eISSN - 1600-0722
pISSN - 0909-8836
DOI - 10.1111/eos.12273
Subject(s) - axin2 , wnt signaling pathway , missense mutation , mutant , beta catenin , mutation , biology , genetics , homeobox , cancer research , microbiology and biotechnology , gene , transcription factor
Tooth agenesis is a congenital anomaly frequently seen in humans. Several genes have been associated with non‐syndromic tooth agenesis, including msh homeobox 1 ( MSX 1 ), paired box 9 ( PAX 9 ), axis inhibition protein 2 ( AXIN 2 ), ectodysplasin A ( EDA ), and wingless‐type MMTV integration site family member 10A ( WNT 10A ). In this study, we investigated a Chinese family with non‐syndromic tooth agenesis. A novel missense mutation (c.C1978T) in AXIN 2 was identified in affected members. The mutation results in a His660Tyr substitution located between the Axin beta‐catenin binding domain and the DIX domain of the axis inhibition protein 2 (AXIN2). We analysed this novel AXIN 2 mutant, together with two reported AXIN 2 mutants [c.1966C>T (p.Arg656Stop) and c.1994delG (p.Leu688Stop)] that cause colorectal cancer with and without oligodontia, to study the effect of the mutant p.His660Tyr on the Wnt/ β ‐catenin signaling pathway and to compare the molecular pathogenesis of different AXIN 2 mutants in tooth agenesis and carcinogenesis. Further in vitro experiments indicated that the mutant p.His660Tyr caused inhibition of the Wnt/ β ‐catenin pathway, and the mutants p.Arg656Stop and p.Leu688Stop resulted in over‐activation of the Wnt/ β ‐catenin pathway. In line with previous AXIN 2 mutation studies, we suggest that AXIN 2 mutations with different levels of severity may have distinct effects on the Wnt pathway and the phenotype of disease. Our study provides functional evidence supporting the notion that both inhibition and over‐activation of the Wnt pathway may lead to tooth agenesis.