On keratin mutations in epidermolytic hyperkeratosis and the regulation of keratin expression by retinoids

Sammanfattning: Epidermolytic hyperkeratosis is a rare inherited disease of the skin caused by a dominant-negative mutation in keratin 1 (K1) or 10 (K10). Keratins are the major structural protein in epidermis and mutations causes instability of intermediate filament and keratinocyte fragility. No curative treatment is available, but some patients benefit from retinoid therapy. More knowledge is needed about the genotype/phenotype correlation in epidermolytic hyperkeratosis and the mechanism of action of retinoids including regulation of keratin expression. Fifteen patients were identified in Scandinavia, 13 with a generalised disease and 2 with localised lesions. Different types of mutation were identified such as point, splice site, deletion, and deletion-insertion mutations. An association was found between mutation in K1 and the appearance of palmoplantar keratoderma. Only the patients with K10 mutation benefited from the treatment, although no differences in the mRNA levels for K1 and K10 were detected. However, retinoids caused a pronounce down-regulation of K2e in upper epidermis and upregulation of K4 not normally present in the skin. This was further investigated in normal healthy skin and in keratinocytes grown in a reconstructed skin model. By adding retinoids with different affinity for the nuclear receptors RAR and RXR to the culture, the most potent retinoids were found to be RARα agonist, the effect of which could be inhibited by addition of a pan RAR antagonist. In conclusion, several novel keratin mutations have been shown to cause epidermolytic hyperkeratosis, and genotype/phenotype correlations have been found. Treatment with retinoids is only useful for patients with a K10 mutation, possibly because they are less vulnerable too the pronounce down-regulation of K2e also seen in normal skin. This effect and the upregulation of K4 seem to be mediated through RARα , expressed in the keratinocytes.