Multiple Milia as an Isolated Skin Manifestation of Dominant Dystrophic Epidermolysis Bullosa: Evidence of Phenotypic Variability.

We report a Japanese pedigree with dominant dystrophic epidermolysis bullosa (DDEB) harboring the p.G2251E mutation of COL7A1. The proband of this pedigree presented with multiple milia as an isolated skin manifestation without a history of blistering and subsequently developed generalized intractable blisters, suggesting that multiple milia could be a primary manifestation of DDEB. Her mother exhibited nail dystrophy and pruritic nodules and her elder sister was unaffected, despite having the same COL7A1 mutation. Inter- and intrafamilial clinical variability are often observed in DDEB, so we should be aware of this factor to provide appropriate genetic counselling.

Calcineurin/NFAT-dependent regulation of 230-kDa bullous pemphigoid antigen (BPAG1) gene expression in normal human epidermal keratinocytes.

BACKGROUND AND OBJECTIVE: Cyclosporin A (CsA) is utilized widely for treatment of inflammatory skin diseases, such as psoriasis vulgaris. The therapeutic effects of CsA are thought to be mediated by its immunosuppressive action on infiltrating lymphocytes in the lesional skin. CsA also inhibits epidermal keratinocyte proliferation, suggesting a direct biological action on keratinocytes. Here we tested the hypothesis that CsA can modulate the expression of the nuclear factor of activated T-cell (NFAT) in epidermal keratinocytes. We also investigated whether the keratinocyte-specific gene expression is modified by CsA through NFAT activity in association with differentiation induction. METHODS: RT-PCR was performed using total RNAs extracted from cultured normal human epidermal keratinocytes (NHEK), normal human dermal fibroblasts (NHDF), and normal human epidermal melanocytes (NHEM) for detecting NFAT isomolecules. Transient transfections of NHEK with a 230-kDa bullous pemphigoid antigen (BPAG1) promoter/luciferase reporter gene and the luciferase assay were conducted for examining the effect of CsA on the promoter activity of the BPAG1 gene. Electrophoretic gel mobility shift assays (EMSA) with probes containing NFAT consensus sequences for analyzing the binding activities of the nuclear proteins extracted from NHEK. RESULTS: RT-PCR revealed expression of all of the five isoforms of NFAT in the cell lines examined. The mRNA expression levels of NFAT1, NFAT2, BPAG1, and involucrin were downregulated by CsA treatment in NHEK. The luciferase assay indicated suppression of the promoter activity by CsA. EMSA with NFAT consensus probes identified in the BPAG1 promoter region demonstrated specific binding activity in the nuclear proteins of epidermal keratinocytes. CONCLUSION: As reported previously, our results indicate that epidermal keratinocytes possess calcineurin/NFAT system, which is suppressed by CsA. In addition, the data suggest that CsA can downregulate the BPAG1 gene expression perhaps via the NFAT consensus cis-elements in the BPAG1 promoter region. Such transcriptional regulatory system might be involved in the regulation of keratinocyte differentiation and proliferation.

Dominant dystrophic epidermolysis bullosa caused by a novel G2037R mutation and by a known G2028R mutation in the type VII collagen gene (COL7A1).

An autosomal dystrophic epidermolysis bullosa (DDEB) is a hereditary mechanobullous disease characterized by blistering of the skin and the mucous membrane. DDEB is caused by a heterozygous mutation in the COL7A1 gene encoding type VII collagen, the major component of anchoring fibrils, and phenotypically classified into several types. We experienced two boys with DDEB and examined the mutation analyses of the COL7A1 genes of the two patients and their fathers to clarify the relationship between the genotypes and phenotypes, that is, the mutation sites of COL7A1 gene and the clinical types of DDEB. The case 1 and 2 patients and their fathers revealed a heterozygous nucleotide G to A transition at position 6109 and 6082 in 73 exon of COL7A1, which resulted in a glycine to arginine substitution (G2037R and G2028R), respectively. G2037R found in the case 1 patient was a novel mutation. There was no clear relationship recognized between the two mutation sites in the COL7A1 gene and the clinical variations.

Novel SLC39A4 mutations in acrodermatitis enteropathica.

Acrodermatitis enteropathica is an autosomal recessive disease characterized by skin involvement due to defective intestinal zinc absorption. Usually, the skin lesions include erythema, erosions, and small blisters in perioral, perianal regions, and hands and feet, which develop soon after weaning from the breast. The acrodermatitis enteropathica gene has been localized to chromosomal region 8q24.3 and subsequently the SLC39A4 gene has been disclosed as the acrodermatitis enteropathica gene. SLC39A4 mutations have been demonstrated in several acrodermatitis enteropathica families, and in this study we have examined two Japanese acrodermatitis enteropathica families for SLC39A4 mutations. The mutation detection strategy consisted of polymerase chain reaction amplification of all 12 exons and flanking intronic sequences, followed by direct nucleotide sequencing. It revealed three novel mutations, 1017ins53, which creates a premature termination codon, and two mis-sense mutations, R95C and Q303H.