Mutational spectrum of the ED1 gene in X-linked hypohidrotic ectodermal dysplasia

Abstract

X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common form of the ectodermal dysplasias characterised by an abnormal development of eccrine sweat glands, hair and teeth. The ED1 gene responsible for the disorder undergoes extensive alternative splicing and to date few studies have concerned the full length transcript. We screened 52 unrelated families or sporadic cases for mutation in the full coding sequence of this gene. SSCA analysis or direct sequencing allowed identification of mutations in 34 families: one initiation defect, twenty-two missenses, two nonsense, eight insertions or deletions, and a large deletion encompassing all the ED1 gene. Fourteen of these mutations have not been previously described, including five missenses. One third of identified mutations were localised in codons 155 and 156, affecting CpG dinucleotides and nine of them correspond to the R156H missense. Hypothesis of a founder effect has been ruled out by haplotype analysis of flanking microsatellites. These recurrent mutations indicate the functional importance of the positively charged domain of the protein. Including our data, there are now 56 different mutations reported in 85 independent patients, that we have tabulated. Review of clinical features in the present series of affected males and female carriers showed no obvious correlation between the type of mutations, the phenotype and its severity. The X-chromosome pattern of inactivation in leucocytes showed little correlation with expressivity of the disease in female carriers. Finally this study is useful for functional studies of the protein and to define a diagnostic strategy for mutation screening of the ED1 gene.

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

“…The spectrum of mutations is comparable to series published before. 9 Mutation screening in the EDAR gene Five of the 18 ED1-negative index patients (28%) had mutations in the EDAR gene. In four of these families, the pedigree was compatible with an autosomal dominant inheritance pattern, and in three of them, we found mutations already described as causing autosomal dominant HED: p.Arg358X in families 3 and 4, and p.Arg420Gln in family 5.…”

Missense mutation of the EDA gene in a Jordanian family with X-linked hypohidrotic ectodermal dysplasia: phenotypic appearance and speech problems

“…XLHED is characterized by reduced sweating (anhidrosis) and heat intolerance, sparse hair (hypotrichosis), and the absence of certain teeth (oligodontia or hypodontia) (Kupietzky and Houpt, 1995;Park et al, 1999). Hemizygous males show severe forms of the disease, while heterozygous females often manifest mild to moderate symptoms because of X-chromosome inactivation (Monreal et al, 1998;Vincent et al, 2001;Sekiguchi et al, 2005;Tao et al, 2006). XLHED is caused by mutations in the EDA gene (Kere et al, 1996;Bayes et al, 1998), which encodes ectodysplasin-A.…”

A novel mutation in the bovine <i>EDA</i> gene causing anhidrotic ectodermal dysplasia (Brief report)

“…In humans, many different mutations within the EDA gene are known to result in phenotypes comparable to the one described herein. Interestingly, one report described two human patients, who also had a C > T transition in codon 244 leading to a truncated protein similar to the genetic lesion observed in the EDA cattle of this study indicating that a similar mutation has occurred independently in cattle and humans (VINCENT et al, 2001). The R244X mutation described in the current report represents the third reported EDA mutation in cattle.…”