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 ec crine sweat glands, hair and teeth. The ED1 gene responsible for the disord er undergoes extensive alternative splicing and to date few studies have co ncerned the full length transcript. We screened 52 unrelated families or sp oradic cases for mutation in the full coding sequence of this gene. SSCA an alysis or direct sequencing allowed identification of mutations in 34 famil ies: one initiation defect, twenty-two missenses, two nonsense, eight inser tions or deletions, and a large deletion encompassing all the ED1 gene. Fou rteen 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 R15 6H missense. Hypothesis of a founder effect has been ruled out by haplotype analysis of flanking microsatellites. These recurrent mutations indicate t he functional importance of the positively charged domain of the protein. I ncluding our data, there are now 56 different mutations reported in 85 inde pendent patients, that we have tabulated. Review of clinical features in th e present series of affected males and female carriers showed no obvious co rrelation between the type of mutations, the phenotype and its severity. Th e X-chromosome pattern of inactivation in leucocytes showed little correlat ion 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.