Two novel mutations in the ED1 gene in Japanese families with X-linked hypohidrotic ectodermal dysplasia.

X-linked hypohidrotic ectodermal dysplasia (XLHED), which is characterized by hypodontia, hypotrichosis, and hypohidrosis, is caused by mutations in ED1, the gene encoding ectodysplasin-A (EDA). This protein belongs to the tumor necrosis factor ligand superfamily. We analyzed ED1 in two Japanese patients with XLHED. In patient 1, we identified a 4-nucleotide insertion, c.119-120insTGTG, in exon 1, which led to a frameshift mutation starting from that point (p.L40fsX100). The patient's mother was heterozygous for this mutation. In patient 2, we identified a novel missense mutation, c.1141G>C, in exon 9, which led to a substitution of glycine with arginine in the TNFL domain of EDA (p.G381R). This patient's mother and siblings showed neither symptoms nor ED1 mutations, so this mutation was believed to be a de novo mutation in maternal germline cells. According to molecular simulation analysis of protein structure and electrostatic surface, p.G381R increases the distance between K375 in monomer A and K327 in monomer B, which suggests an alteration of overall structure of EDA. Thus, we identified two novel mutations, p.L40fsX100 and p.G381R, in ED1 of two XLHED patients. Simulation analysis suggested that the p.G381R mutation hampers binding of EDA to its receptor via alteration of overall EDA structure.