We have previously clone a human gene (P) and have detected mutations of this gene in the mouse homolog (p) and in human patients with tyrosinase- positive (type II) oculocutaneous albinism (Ty+-OCA). This gene appears to be expressed specifically in human melanocytes and mouse skin producing eumelanin (black-brown) pigment. More recently, we have observed that the P gene is surprisingly closely related to a gene from Mycobacterium leprae, a bacterium that produces melanin. Furthermore, several other bacterial pump proteins have statistically significant homologies to P, and at least in the mouse, we have detected a closely related gene to the P gene. Based on the phenotypic effect of P/p mutations, the biologics of melanin production, and the predicted amino acid sequence of the P gene which suggests an integral membrane protein with 12 transmembrane domains, we hypothesize that the P polypeptide is a tyrosine transporter and that disturbances in this protein product will have important implications for human dermatologic conditions such as leprosy and certain types of chemical depigmentation, dermatological disease in which pigmentary abnormalities are a prominent manifestation. There are three specific aims in this proposal: (1) To raise polyclonal (and monoclonal) antibodies to the human P polypeptide; (2) To use these antibodies for immunocytochemical localization of the P polypeptide in cellular membranes and the histological examination of different tissues. These antibodies will also be useful to examine the potential role of the P poly-peptide in various pigmentary pathological states; (3) To construct a functional P expression vector and to assay aromatic amino acid transport, including tyrosine, by the P polypeptide. The preliminary data obtained from these studies should shed light into the biology of pigmentation and its disturbances in inherited and acquired dermatologic conditions.
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