Loricrin is a major constituent of the epidermal cornified cell envelope. We have recently identified heterozygous
loricrin gene mutations in two dominantly inherited
skin diseases, the ichthyotic variant of
Vohwinkel syndrome and progressive symmetric erythrokeratoderma, collectively termed
loricrin keratoderma. In order to see whether the mutant
loricrin molecules predicted by
DNA sequencing are expressed in vivo and to define their pathologic effects, we raised
antibodies against synthetic
peptides corresponding to the mutated sequences of
loricrin. Immunoblotting of horny
cell extracts from
loricrin keratoderma patients showed specific bands for mutant
loricrin. Immunohistochemistry of
loricrin keratoderma skin biopsies showed positive immunoreactivity to the mutant
loricrin antibodies in the nuclei of differentiated epidermal keratinocytes. The immunostaining was localized to the nucleoli of the lower granular cell layer. As keratinocyte differentiation progressed the immunoreactivity moved gradually into the nucleoplasm leaving nucleoli mostly nonimmunoreactive. No substantial staining was observed along the cornified cell envelope. This study confirmed that mutant
loricrin was expressed in the
loricrin keratoderma skin. Mutant
loricrin, as a dominant negative disrupter, is not likely to affect cornified cell envelope crosslinking directly, but seems to interfere with nuclear/nucleolar functions of differentiating keratinocytes. In addition, detection of the mutant
loricrin in scraped horny layer could provide a simple noninvasive screening test for
loricrin keratoderma. J Invest Dermatol 115:1088-1094 2000