Mutations in the cornified cell envelope
protein loricrin have been reported recently in some patients with
Vohwinkel syndrome (VS) and progressive symmetric erythrokeratoderma (PSEK). To establish a causative relationship between
loricrin mutations and these diseases, we have generated transgenic mice expressing a COOH-terminal truncated form of
loricrin that is similar to 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 scaling 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 mice also showed retention of nuclei in the stratum corneum, a characteristic feature of VS and PSEK. Immunofluorescence and immunoelectron microscopy showed the mutant
loricrin protein in the nucleus and cytoplasm of epidermal keratinocytes, but did not detect the
protein in the cornified cell envelope. Transfection experiments indicated that the COOH-terminal domain of the mutant
loricrin contains a
nuclear localization signal. To determine whether the ML.VS phenotype resulted from dominant-negative interference of the transgene with endogenous
loricrin, we mated the ML.VS transgenics with
loricrin 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. Longley, J. Bickenbach, Y. Kawachi, Y. Suga, Z. Zhou, M. Huber, et al., J. Cell Biol. 151:389-400, this issue), this phenotype may be attributed to expression of the mutant form of
loricrin. Thus, deposition of the
mutant protein in the nucleus appears to interfere with late stages of epidermal differentiation, resulting in a VS-like phenotype.