Possible role for protein kinase C in the pathogenesis of inborn errors of metabolism

Protein kinase C (PKC) is a ubiquitous enzyme family implicated in the regulation of a large number of short‐ and long‐term intracellular processes. It is hypothesized that modulation of PKC activity may represent, at least in part, a functional link between mutations (genotype) that lead to the pathological accumulation of naturally occurring compounds that affect PKC activity and perturbation of PKC‐mediated substrate phosphorylation and cellular function in the corresponding diseases (phenotype). This model provides a unifying putative mechanism by which the phenotypic expression of some inborn errors of metabolism may be explained. Recent studies in a cell‐free system of human skin fibroblasts support the hypothesis that alteration of PKC activity may represent the functional link between accumulation of sphingolipids and fatty acyl‐CoA esters, and perturbation of cell function in sphingolipidoses and fatty acid oxidation defects, respectively. Further studies will elucidate the effects of these alterations on PKC‐mediated short‐ and long‐term cellular functions in these diseases, as well as the possible role of PKC in the pathogensis of other diseases. © 1995 Wiley‐Liss, Inc.