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

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.