Transgenic mice expressing a mutant form of loricrin reveal the molecular basis of the skin diseases, Vohwinkel syndrome and progressive symmetric erythrokeratoderma

Mutations in the cornified cell envelope protein loricrin have been reporte d recently in some patients with Vohwinkel syndrome (VS) and progressive sy mmetric erythrokeratoderma (PSEK). To establish a causative relationship be tween loricrin mutations and these diseases, we have generated transgenic m ice expressing a COOH-terminal truncated form of loricrin that is similar t o the protein expressed in VS and PSEK patients. At birth, transgenic mice (ML.VS) exhibited erythrokeratoderma with an epidermal barrier dysfunction. 4 d after birth, high-expressing transgenic animals showed a generalized s caling of the skin, as well as a constricting band encircling the tail and, by day 7, a thickening of the footpads. Histologically, ML.VS transgenic m ice also showed retention of nuclei in the stratum corneum, a characteristi c feature of VS and PSEK, Immunofluorescence and immunoelectron microscopy showed the mutant loricrin protein in the nucleus and cytoplasm of epiderma l keratinocytes, but did not detect the protein ill the cornified cell enve lope. Transfection experiments indicated that the COOH-terminal domain of t he mutant loricrin contains a nuclear localization signal. To determine whe ther the ML.VS phenotype resulted from dominant-negative interference of th e transgene with endogenous loricrin, we mated the ML.VS transgenics with l oricrin knockout mice. A severe phenotype was observed in mice that lacked expression of wild-type loricrin. Since loricrin knockout mice are largely asymptomatic (Koch, P.K., P.A. de Viragh, E. Scharer, D. Bundman, M.A. Long ley, J. Bickenbach, Y. Kawachi, Y. Suga, 2. Zhon, M. Huber, et al., J. Cell Biol. 152:389-400, this issue), this phenotype may be attributed to expres sion of the mutant form of loricrin. Thus, deposition of the mutant protein in the nucleus appears to interfere with late stages of epidermal differen tiation, resulting in a VS-like phenotype.