S7-6 Wed Jan 6 14:30 – 03:00 Melanosome protein contents and oculocutaneous albinism: The importance of remaining neutral Marks, MS; Children’s Hospital of Philadelphia and University of Pennsylvania email@example.com https://www.med.upenn.edu/markslab/
Melanins in mammals are critical for photoprotection of the hair and skin and for proper retinal development and function. Melanins are synthesized within skin and eye pigment cells within specialized lysosome-related organelles called melanosomes. Defects in melanosome maturation or contents result in oculocutaneous albinism (OCA), characterized by hypopigmentation of the hair, skin and eyes, poor visual acuity, and additional ocular symptoms. Non-syndromic albinism results from defects in at least eight distinct genes, most of which encode melanosome membrane proteins. Several of these are key enzymes in melanogenesis, including tyrosinase (TYR), TYRP1 and DCT (mutated in OCA type 1, 3 and 8). Two others – OCA2 and SLC45A2 (targeted in OCA types 2 and 4) – are ion permeases that help neutralize the low pH of immature melanosomes as they mature within melanocytes. This neutralization is required for the pH-sensitive TYR to become active and initiate melanin synthesis. The products of several other more broadly expressed genes, including the chloride channel CLCN7 and the cation channel TPC2, are also disrupted in pigmentary disorders and appear to directly control melanosome pH. In addition, genetic analyses of skin pigment variation among African populations have identified additional genes whose products might indirectly influence melanosome ion content or pH, such as the lysosomal transporter MFSD12. These observations highlight the importance of controlling the ionic environment of melanosomes (and lysosomes) to neutralize the acidic pH of melanosome precursors and thereby support melanin synthesis.