The pink-eyed dilution locus controls the biogenesis of melanosomes and levels of melanosomal proteins in the eye

The pink-eyed dilution (p) locus is known to control the quantity of melani n pigment made within melanocytes and retinal pigment epithelium (RPE) in t he eye. We have examined the effects of several mutant allele combinations at the murine p locus on the number and morphology of melanosomes in choroi dai melanocytes and RPE cells as well as on the levels of four proteins kno wn to be present within melanosomes: tyrosinase, tyrosinase-related protein s 1 and 2 (TRP-1 and TRP-2) and lysosome associated membrane protein-1 (LAM P-1). By electron microscopy, we observed a modest diminution in the size a nd number of choroidal melanosomes in p(bx)/p(J) mice but a more dramatic d ecrease in the RPE in comparison with wild-type P/P mice. By contrast. a dr astic reduction in melanosome size and number was present in the choroid an d RPE of p(un)/p(un) and p(6H)/p(cp) mice, and in the RPE of p(6H)/p(cp) mi ce, melanosomes were essentially undetectable. In wild-type mice, levels of tyrosinase. TRP-1 and TRP-2 were high at birth and showed a second peak of expression at 10-14 days of age. declining to undetectable levels by 42 da ys. All three mutant allele combinations reduced the levels of these melano somal proteins with the relative severity of effects being p(6H)/p(cp) > p( un)/p(un) > p(bx)/p(J) In the null p(6H)/p(cp) mice, levels of these protei ns were extremely low at birth, no postnatal peak was observed, and levels declined to undetectable by 14 days. Levels of LAMP-1 in wild-type mice ros e initially and then declined whereas in the mutant mice. levels decreased gradually from birth. Higher levels of LAMP-1 were observed in each of the mutants than in the wild-type mice at 21 days of age. Our results demonstra te that mutations at the p locus affect the size, number, shape and content s of melanosomes. implicating the p gene product in the normal biogenesis o f this organelle. (C) 1999 Academic Press.