A 92-kD transglutaminase (TGase K), expressed in human cultured keratinocytes and stratum corneum, catalyzes a critical step in the formation of the cornified envelope of terminal differentiation. A rabbit polyclonal antibody to TGase K was used to isolate overlapping cDNA clones from a human keratinocyte cDNA expression library. The cDNA clones were sequenced and unequivocally identified as TGase K by comparison to the N-terminal amino acid sequences of two cyanogen bromide fragments from the purified enzyme. The mRNA for Tgase K is expressed in cultured keratinocytes but not in A431 squamous carcinoma cells, in fibroblasts, or in other non-epithelial tissues and cells. Although TGase K protein expression is limited to the upper layers of normal epidermis, the mRNA is generally present throughout the epidermis, suggesting the possibility of post-transcriptional regulation. Precocious expression of TGase K protein occurs in psoriasis, and quantitative Northern blot analysis of TGase K mRNA from normal and involved epidermal biopsies from psoriasis patients suggests that TGase K mRNA levels are increased in psoriatic lesions. By using quantitative laser scanning confocal microscopy (LSCM) and in situ hybridization, the increase of the TGase K mRNA was in the range of 3-7 times in the psoriatic epidermis and was significantly higher compared with normal skin and with paired adjacent skin. Quantitative LSCM provides a powerful and direct method for analysis of gene expression in skin.