A TRANSGENIC MOUSE MODEL THAT RECAPITULATES THE CLINICAL-FEATURES OF BOTH NEONATAL AND ADULT FORMS OF THE SKIN-DISEASE EPIDERMOLYTIC HYPERKERATOSIS

Keratins are the major structural proteins of keratinocytes, which are the most abundant cell type in the mammalian epidermis. Mutations in epidermal keratin genes have been shown to cause severe blistering ski n abnormalities. One such disease, epidermolytic hyperkeratosis (EHK), also known as bullous congenital ichthyosiform erythroderma, occurs a s a result of mutations in highly conserved regions of keratins K1 and K10. Patients with EHK first exhibit erythroderma with severe blister ing, which later is replaced by thick patches of scaly skin. To assess the effect of a mutated K1 gene on skin biology and to produce an ani mal model for EHK, we removed 60 residues from the 2B segment of HK1 a nd observed the effects of its expression in the epidermis of transgen ic mice. Phenotypes of the resultant mice closely resembled those obse rved in the human disease, first with epidermal blisters, then later w ith hyperkeratotic lesions. In neonatal mice homozygous for the transg ene, the skin was thicker, with an increased labeling index, and the s pinous cells showed a collapse of the keratin filament network around the nuclei, suggesting that a critical concentration of the mutant HK1 , over the endogenous MK1, was required to disrupt the structural inte grity of the spinous cells. Additionally, footpad epithelium, which is devoid of hair follicles, showed blistering in the spinous layer, sug gesting that hair follicles can stabilize or protect the epidermis fro m trauma. Blisters were not evident in adult mice, but instead they sh owed a thick, scaly hyperkeratotic skin with increased mitosis, result ing in an increased number of corneocytes and granular cells. Irregula rly shaped keratohyalin granules were also observed. To date, this is the only transgenic model to show the typical morphology found in the adult form of EHK.