Non-Syndromic Tooth Agenesis in Two Chinese Families Associated with Novel Missense Mutations in the TNF Domain of EDA (Ectodysplasin A)

Shufeng Li,Jiahuang Li,Meng Chen,Qingang Hu,Zi-Chun Hua,Bingrong Zhou,Jian Cheng,Zixing Wang,Xiangbai Dong,Xin Tong

doi:10.1371/journal.pone.0002396

Abstract

Here we report two unrelated Chinese families with congenital missing teeth inherited in an X-linked manner. We mapped the affected locus to chromosome Xp11-Xq21 in one family. In the defined region, both families were found to have novel missense mutations in the ectodysplasin-A (EDA) gene. The mutation of c.947A>G caused the D316G substitution of the EDA protein. The mutation of c.1013C>T found in the other family resulted in the Thr to Met mutation at position 338 of EDA. The EDA gene has been reported responsible for X-linked hypohidrotic ectodermal dysplasia (XLHED) in humans characterized by impaired development of hair, eccrine sweat glands, and teeth. In contrast, all the affected individuals in the two families that we studied here had normal hair and skin. Structural analysis suggests that these two novel mutants may account for the milder phenotype by affecting the stability of EDA trimers. Our results indicate that these novel missense mutations in EDA are associated with the isolated tooth agenesis and provide preliminary explanation for the abnormal clinical phenotype at a molecular structural level.

Highlights

Tooth development is a complex process with reciprocal interactions between the dental epithelium and mesenchyme; many transcription factors and signaling molecules are involved to guide this process
We identify two novel mutations in the EDA gene in two independent Chinese families with isolated tooth agenesis
Both mutations are predicted to result in changes in single amino acid residues in the tumor necrosis factor (TNF) domain of the protein: p.D316G and p.T338M

Summary

Introduction

Tooth development is a complex process with reciprocal interactions between the dental epithelium and mesenchyme; many transcription factors and signaling molecules are involved to guide this process. Mutations in two transcription factor genes, PAX9 (14q12– 13) and MSX1 (4p16.1), have been shown as the major causes of nonsyndromic oligodontia. Mutations in MSX1 coding regions cause human tooth agenesis of various types of teeth, preferentially premolars [2]. PAX9 belongs to the PAX gene family, which encodes a group of transcription factors that play a role in early development. Mutations in PAX9 coding regions or a PAX9 deletion causes preferential tooth agenesis of molars [4,5,6,7,8,9]. In addition to PAX9 and MSX1, AXIN2, which encodes a Wnt-signaling regulator, is reported to associate with oligodontia and colorectal neoplasia [10,11]

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