X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein.

Ectodermal dysplasias comprise over 150 syndromes of unknown pathogenesis. X-linked anhidrotic ectodermal dysplasia (EDA) is characterized by abnormal hair, teeth and sweat glands. We now describe the positional cloning of the gene mutated in EDA. Two exons, separated by a 200-kilobase intron, encode a predicted 135-residue transmembrane protein. The gene is disrupted in six patients with X;autosome translocations or submicroscopic deletions; nine patients had point mutations. The gene is expressed in keratinocytes, hair follicles, and sweat glands, and in other adult and fetal tissues. The predicted EDA protein may belong to a novel class with a role in epithelial-mesenchymal signalling.

Tissue distribution and cell type-specific expression of p120ctn isoforms.

Cadherin-based molecular complexes play a major role in cell-cell adhesion. At the adherens junctions the intracellular domain of cadherins specifically interacts with beta-catenin and p120ctn, members of the Armadillo repeat protein family. Differential splicing and utilization of the alternative translation initiation codons lead to many p120ctn isoforms. Two major p120ctn isoforms are expressed in mouse tissues. In this study we used indirect immunofluorescence to demonstrate significant tissue specificity in expression of the p120ctn isoforms. The short isoform is abundant at cell-cell adhesion junctions in epidermis, palatal, and tongue epithelia, in the ducts of excretory glands, bronchiolar epithelium, and in mucosal epithelia of esophagus, forestomach, and small intestine. In contrast, the long isoform, containing an amino terminus highly conserved within the p120ctn subfamily, is expressed at vascular-endothelial cell junctions in blood vessels, at cell-cell junctions in the serosal epithelium lining the internal organs, in choroid plexus of brain, in the pigment epithelium of retina, and in structures such as the outer limiting membrane of retina and intercalated discs of cardiomyocytes. The tissue- and cell type-specific expression of p120ctn isoforms suggests a role for the long p120ctn isoform in cell structures responsible for stable tissue integrity, compared to the role of the short isoform in cell-cell adhesion in the external epithelia with rapid turnover.

The gene defective in anhidrotic ectodermal dysplasia is expressed in the developing epithelium, neuroectoderm, thymus, and bone.

Anhidrotic ectodermal dysplasia (EDA) is characterized by defects in the development of teeth, hair, and sweat glands. To study the expression of the human gene defective in EDA in human fetal development (Weeks 6-23 of gestational age) and in adult tissues, in situ hybridization and immunohistochemistry were used. First signs of expression were detected at Week 8 in epidermis and in neuroectodermal cells. Starting at Week 12, osteoblasts and thymus were positive for EDA mRNA. Hair follicles expressed EDA mRNA from 18 weeks. The presence of the EDA protein coincided with mRNA expression in the tissues examined. The expression pattern of the EDA gene is consistent with typical involvement of the skin in the syndrome. However, the expression is not limited to the ectodermal tissues and many sites of expression are not obviously reflected in the clinical features of the syndrome.

Cyclosporine in the treatment of palmoplantar pustulosis. A randomized, double-blind, placebo-controlled study.

BACKGROUND AND DESIGN: Palmoplantar pustulosis (PPP) is an inflammatory skin disease characterized by pustule formation, erythema, induration, and scaling of the affected skin of the palms and soles. Palmoplantar pustulosis is usually resistant to treatment. In a double-blind study (phase 1) of 4 weeks, 40 patients with PPP were randomized to receive oral cyclosporine, 2.5 mg/kg per day, or placebo. An open-label dose-finding phase 2 with cyclosporine doses of 1.25, 2.5, and 3.75 mg/kg per day was performed in the following 3 months. The patients were then followed for at least 2 months after termination of cyclosporine treatment. Response to treatment was judged by the number of fresh pustules. Patients displaying a reduction of 50% or greater in the number of pustules, compared with baseline, were defined as responders. RESULTS: Of the patients who completed phase 1, 17 of 19 patients in the cyclosporine group and four of 15 in the placebo group were classified as responders (P < .001). Cyclosporine, but not placebo, significantly reduced formation of new pustules (P = .001). In the subsequent open phase, a daily cyclosporine dose of 1.25 mg/kg appeared to be an effective treatment of PPP in approximately half of the treated patients. Many patients relapsed after initial success with cyclosporine. However, only one patient studied totally failed to respond to cyclosporine treatment. At the end of phase 3, most of the studied parameters had returned to pretreatment levels. The most common side effect was headache in the 2.5 mg/kg per day dosage group; no significant side effects were observed in the 1.25 mg/kg per day dosage group. CONCLUSIONS: Low-dose cyclosporine treatment (1.25 to 2.5 mg/kg per day) is effective in PPP.

Expression of the anhidrotic ectodermal dysplasia gene is reduced in skin cancer coinciding with reduced E-cadherin.

X-linked anhidrotic ectodermal dysplasia (EDA) is characterized by defects in the development of hair, teeth, and sweat glands. We have recently cloned the gene for EDA by positional cloning. The EDA gene encodes a transmembrane protein with a putative role in epithelial mesenchymal interactions. Since EDA could play a role in cell-cell or cell-matrix adhesion, acantholytic skin diseases and several types of non-invasive and invasive skin cancers were studied using in situ hybridization. Because of the observation that the promoter region of the EDA gene contains a binding site for LEF-1, which is involved in the signaling through E-cadherin/beta catenin complex, we compared the expression of EDA with immunolocalization for E-cadherin (E-CD). EDA expression during hair growth cycle, in benign adnexal tumors, and neuroectoderm-derived nevus cells was also examined. Our findings indicate that EDA expression is less abundant in malignant tumors, including basal and squamous cell carcinomas and melanoma, and in acantholytic keratinocytes compared to normal epidermis. The reduction in expression also coincides with diminished E-CD staining in all malignant cell types and in acantholytic cells. Our results suggest that EDA protein functions in the regulation of epithelial cell contacts and that it may be associated with the E-CD signaling pathway.

Fine mapping of the EDA gene: a translocation breakpoint is associated with a CpG island that is transcribed.

In order to identify the gene for human X-linked anhidrotic ectodermal dysplasia (EDA), a translocation breakpoint in a female with t(X;1)(q13.1;p36.3) and EDA (patient AK) was finely mapped. The EDA region contains five groups of rare-cutter restriction sites that define CpG islands. The two more centromeric of these islands are associated with transcripts of 3.5 kb and 1.8 kb. The third CpG island maps within <1 kb of the translocation breakpoint in patient AK, as indicated by a genomic rearrangement, and approximately 100 kb centromeric from another previously mapped translocation breakpoint (patient AnLy). Northern analysis with a probe from this CpG island detected an approximately 6-kb mRNA in several fetal tissues tested. An extended YAC contig of 1,200 kb with an average of fivefold coverage was constructed. The two most telomeric CpG islands map 350 kb telomeric of the two translocations. Taken together, the results suggest that the CpG island just proximal of the AK translocation breakpoint lies at the 5' end of a candidate gene for EDA.