Two Novel Mutations in the ED1 Gene in Japanese Families With X-Linked Hypohidrotic Ectodermal Dysplasia

Abstract

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.1141GϾC, 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. (Pediatr Res 65: 453-457, 2009) H ypohidrotic ectodermal dysplasia (HED) is a congenital disorder characterized by the impaired development of teeth (hypodontia), hair (hypotrichosis), and eccrine sweat glands (hypohidrosis) (1). Most HED patients have shown an X-linked inheritance pattern, although a minority of patients had an autosomal dominant or recessive trait (2,3).The ED1 gene responsible for XLHED was mapped to chromosome Xq12-q13 and was identified by positional cloning (4). ED1 encodes the protein ectodysplasin-A (EDA) that belongs to the tumor necrosis factor ligand (TNFL) superfamily (5,6). EDA consists of a small N-terminal intracellular domain, a transmembrane domain, and a larger C-terminal extracellular domain containing a furin-cleavage site, a collagen-like domain, and a TNFL domain. The collagen-like domain has been believed to be necessary for trimerization of EDA proteins (7). However, it is not known whether the collagen-like domain is solely responsible for the trimerization: constructs of EDA-A1 and EDA-A2 lacking the collagenlike region can pack in the crystals as dimers of trimers (8). The TNFL domain has the ability to interact with the EDA receptor (EDAR) and X-linked ectodysplasin-A2 receptor (XEDAR) (9).EDA-A1 and EDA-A2 are the longest EDA isoforms, but they differ by only an insertion/deletion of two amino acids (E308, V309) as determined by alternative splicing of ED1 pre-mRNA. This insertion/deletion functions to regulate receptor-binding specificity, such that EDA-A1 binds EDAR, whereas EDA-A2 binds XEDAR (10). EDAR interacts with its adapter EDAR-associated death domain (EDARADD) to build an intracellular complex and activate the nuclear factor-B pathway, which is essen...

X-Linked Hypohidrotic Ectodermal Dysplasia: New Features and a Novel <b><i>EDA</i></b> Gene Mutation

“…The identification of female carriers of XLHED can be difficult because of the variety of clinical features due to the X-chromosome inactivation, generally that one carrying the wild-type allele [Gunadi et al, 2009]. First, Lexner et al [2007] showed that dental anomalies, salivary flow and composition may be used as a part of a comprehensive clinical examination to identify potential female carries of XLHED [Lexner et al, 2007].…”

Orofacial Features of Hypohidrotic Ectodermal Dysplasia

“…Dental abnormalities (hypodontia, microdontia, cone-shaped incisors), mild hypohidrosis, and mild hypotrichosis are the most commonly described signs in female carriers of XLHED [22]. It is widely believed that these linear characteristics of XLHED in female carriers of EDA mutations are the result of preferential inactivation of one X chromosome carrying the wild-type allele [23].…”

NRG1 variant effects in patients with Hirschsprung disease

“…The products were separated and analyzed on a 3730xl Genetic Analyzer (Applied Biosystems, Foster City, CA) using DNA Sequencing Analysis Software (Applied Biosystems, Foster City, CA) [17, 18]. …”