The pink-eyed dilution (p) gene plays a central role in the control of human pigmentation. Mutations in the p gene cause oculocutaneous albinism type 2 and other forms hypopigmentation, and polymorphisms in the p gene have been associated with normal variations in skin and eye color. We propose to concentrate our efforts on the study of the biology and function of the pink-eyed dilution gene product and the control of tyrosinase processing. During the next period of support, three major specific aims will be pursued. We will: *Explore by cellular, molecular and genetic approaches the role of the p gene product in tyrosinase processing and trafficking in melanocytic and nonmelanocytic cells. *Evaluate the subcellular effects of and targets for pharmacologic agents that can correct for the lack of p expression in melanocytic and nonmelanocytic cells. *Examine the role of glutathione in tyrosinase processing and the role of the p gene product in melanocyte glutathione metabolism and redox using both mammalian and yeast-based systems, and a combination of cellular, molecular, pharmacologic and genetic techniques. We believe that the proposed experimentation will greatly advance our understanding of the pathogenesis of OCA2, of normal variations in ethnic skin coloration, and of pigmentary defects in amelanotic melanomas, in addition to furthering our knowledge regarding the normal cellular and molecular process of pigmentation. Moreover, our results are likely to result directly in potential pharmacologic therapies of OCA2.
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