CONSEQUENCES OF BETA-GLUCOCEREBROSIDASE DEFICIENCY IN EPIDERMIS - ULTRASTRUCTURE AND PERMEABILITY BARRIER ALTERATIONS IN GAUCHER DISEASE

Hydrolysis of glucosylceramide by beta-glucocerebrosidase results in c eramide, a critical component of the intercellular lamellae that media te the epidermal permeability barrier. A subset of type 2 Gaucher pati ents displays ichthyosiform skin abnormalities, as do transgenic Gauch er mice homozygous for a null allele. To investigate the relationship between glucocerebrosidase deficiency and epidermal permeability barri er function, we compared the stratum corneum (SC) ultrastructure, lipi d content, and barrier function of Gaucher mice to carrier and normal mice, and to hairless mice treated topically with bromoconduritol B ep oxide (BrCBE), an irreversible inhibitor of glucocerebrosidase. Both G aucher mice and BrCBE-treated mice revealed abnormal, incompletely pro cessed, lamellar body-derived sheets throughout the SC interstices, wh ile transgenic carrier mice displayed normal bilayers. The SC of a sev erely affected type 2 Gaucher's disease infant revealed similarly abno rmal ultrastructure. Furthermore, the Gaucher mice demonstrated marked ly elevated transepidermal water loss (4.2+/-0.6 vs < 0.10 g/m(2) per h). The electron-dense tracer, colloidal lanthanum, percolated between the incompletely processed lamellar body-derived sheets in the SC int erstices of Gaucher mice only, demonstrating altered permeability barr ier function. Gaucher and BrCBE-treated mice showed < 1% and < 5% of n ormal epidermal glucocerebrosidase activity, respectively, and the epi dermis/SC of Gaucher mice demonstrated elevated glucosylceramide (5- t o 10-fold), with diminished ceramide content. Thus, the skin changes o bserved in Gaucher mice and infants may result from the formation of i ncompetent intercellular lamellar bilayers due to a decreased hydrolys is of glucosylceramide to ceramide. Glucocerebrosidase therefore appea rs necessary for the generation of membranes of sufficient functional competence for epidermal barrier function.