Mutation screening of the Ectodysplasin-A receptor gene EDAR in hypohidrotic ectodermal dysplasia

Abstract

Hypohidrotic ectodermal dysplasia (HED) can be caused by mutations in the X-linked ectodysplasin A (ED1) gene or the autosomal ectodysplasin A-receptor (EDAR) and EDAR-associated death domain (EDARADD) genes. X-linked and autosomal forms are sometimes clinically indistinguishable. For genetic counseling in families, it is therefore important to know the gene involved. In 24 of 42 unrelated patients with features of HED, we found a mutation in ED1. ED1-negative patients were screened for mutations in EDAR and EDARADD. We found mutations in EDAR in 5 of these 18 patients. One mutation, p.Glu354X, is novel. In EDARADD, a novel variant p.Ser93Phe, probably a neutral polymorphism, was also found. Clinically, there was a difference between autosomal dominant and autosomal recessive HED patients. The phenotype in patients with mutations in both EDAR alleles was comparable to males with X-linked HED. Patients with autosomal dominant HED had features comparable to those of female carriers of X-linked HED. The teeth of these patients were quite severely affected. Hypohidrosis and sparse hair were also evident, but less severe. This study confirms Chassaing et al's earlier finding that mutations in EDAR account for approximately 25% of non-ED1-related HED. Mutations leading to a premature stop codon have a recessive effect except when the stop codon is in the last exon. Heterozygous missense mutations in the functional domains of the gene may have a dominant-negative effect with much variation in expression. Patients with homozygous or compound heterozygous mutations in the EDAR gene have a more severe phenotype than those with a heterozygous missense, nonsense or frame-shift mutation.

Hypohydrotic Ectodermal Dysplasia in Black Africans

“…The first cases of ED seen in our hospital and referred to our department were a set of identical female twin with autosomal recessive manifestation (14). However, the X-linked EDA and the autosomal form may sometimes be indistinguishable clinically while the autosomal dominant HED is readily differentiated from autosomal recessive disease clinically (9).…”

Effects of an Asian-specific nonsynonymous EDAR variant on multiple dental traits

“…17,18 In humans, loss-of-function mutations of this gene result in hypohidrotic ectodermal dysplasia (MIM 129490, 224900 and 305100), which is a genetic disorder that results in congenital defects in tissues and structures of ectodermal origin such as teeth, nails, sweat glands and hair. 19,20 Animal models have also suggested that the EDA/EDAR pathway regulates the development of ectodermal derivative. [21][22][23][24][25][26][27][28][29] It is also worth noting that, in studies on human population genetics, a strong signal of positive selection in Asian populations has been observed for the EDAR 370A allele.…”

Orofacial Features of Hypohidrotic Ectodermal Dysplasia

“…The most prevalent form of HED is X-linked hypohidrotic ectodermal dysplasia (XLHED); however, some families show autosomal dominant or recessive inheritance forms of the disorder [4,5]. The incidence of HED is estimated to be 1 per 100,000 births.…”

“…It is characterized by absence or a diminished number of eccrine sweat glands, missing and malformed teeth, and thin and sparse hair. The severity of symptoms can vary between and within families [5,6].…”

“…The gene responsible for XLHED is localized at Xq12-q13.1 that is associated with the EDA gene, which codes for a transmembrane protein that is expressed by keratinocytes, hair follicles, teeth, and sweat glands. This gene may play a key role in epithelial-mesenchymal signaling, leading to the clinical aspects of the disorder [5,[12][13][14].…”