We used Tyr c-2J/c-2J as a model for OCA1a. These mice are white with pink eyes due to a missense mutation in tyrosinase that is null at the protein level. We used Tyr c-h/c-h (Himalayan) mice as our model of OCA1b. These mice have an off-white coat color, reduced ocular pigmentation and pigmentation in their extremities due to a mutation that produces a heat-labile form of tyrosinase. We successfully obtained independent grant funding from the Blind Childrens Center for our pilot experiments. Nitisinone treatment resulted in a 6-fold and a 4-fold increase in steady-state plasma tyrosine concentrations in Tyrc-2J/c-2J and Tyrc-h/c-h mice, respectively. After one month of nitisinone treatment, C57BL6-Tyr c-h/ch mice, but not C57BL6-Tyr c-2J/c-2J mice, showed a visible increase in coat and iris pigmentation. Neither vehicle-treated group showed any change in pigmentation. (Because pigment is preferentially deposited in growing hair, a patch of each mouses coat was shaved immediately prior to initiating nitisinone treatment.) Electron microscopy studies revealed a statistically-significant difference in the number of pigmented (stage III and IV) melanosomes in the RPE, choroid and iris of treated C57BL6-Tyr c-h/ch mice. No difference was observed in C57BL6-Tyr c-2J/c-2J mice or in vehicle treated mice. Maternal treatment during pregnany of Tyr c-h/c-h females leads to an increase in pigmentation of pups when they are born. We have performed both in silico and in vitro studies of the c-2J and c-h mutant proteins and demonstrated that the latter responds to increased tyrosine. This work has been accepted for publication in the Journal of Clinical Investigation. An NIH Director's Award Challenge Grant was received near the end of FY2011 to help proceed with this work.
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