Novel EDA p.Ile260Ser mutation linked to non-syndromic hypodontia.

Hypodontia, a tooth developmental disease, can affect chewing and pronunciation. Mutations in the ectodysplasin-A (EDA) gene can lead to both X-linked hypohidrotic ectodermal dysplasia (XLHED) and non-syndromic hypodontia (NSH). However, the mechanism by which these 2 related but different disorders are caused by the distinct mutations in EDA is unknown. In this study, we identified a novel missense mutation (c.779 T>G) in a Chinese family with NSH via a direct sequencing approach. This mutation results in an Ile260Ser substitution in the tumor necrosis factor (TNF) homology domain. Homology modeling suggests that this alteration may induce a conformational change in the hydrophobic center of the TNF homology domain. Furthermore, by exploring systematic 3D conformation analysis and calculation of residue relative solvent accessibility (RSA) for all the reported mutated amino acid sites on EDA's TNF homology domain, we found that the site mutations at the interior may be linked to XLHED, while those at the surface are more likely to be associated with NSH. These findings may aid in the discovery of unidentified functionally significant mutation sites in the EDA gene and provide a new way to clarify the mechanisms by which the XLHED and NSH phenotypes arise from mutations in the same gene.