The mouse p (pink-eyed dilution) and human P genes, oculocutaneous albinism type 2 (OCA2), and melanosomal pH

Recessive mutations of the mouse p (pink-eyed dilution) gene lead to hypopi gmentation of the eyes, skin, and fur. Mice lacking a functional p protein have pink eyes and light gray fur (if non-agouti) or cream-colored fur (if agouti), The human orthologue is the P protein. Humans lacking a functional P protein have oculocutaneous albinism type 2 (OCA2), Melanocytes from p-d eficient mice or OCA2 individuals contain small, minimally pigmented melano somes. The mouse and human proteins are predicted to have 12 membrane spann ing domains and possess significant sequence homology to a number of membra ne transport proteins, some of which are involved in the transport of anion s, The p protein has been localized to the melanosome membrane. Recently, i t has been shown that melanosomes from p protein-deficient melanocytes have an abnormal pH. Melanosomes in cultured melanocytes derived from wild-type mice are typically acidic, whereas melanosomes from p protein-deficient mi ce are nonacidic. Melanosomes and related endosome-derived organelles (i.e. , lysosomes) are thought to have an adenosine triphosphate (ATP)-driven pro ton pump that helps to generate an acidic lumen, To compensate for the char ge of these protons, anions must also be transported to the lumen of the me lanosome. In light of these observations, a model of p protein function is presented in which the p protein, together with the ATP-driven proton pump, regulates the pH of the melanosome.