Our previously-reported work on OCA1A and OCA1B mouse models has been published in the Journal of Clinical Investigation. This work established the nitisinone could increase melanin pigmentation in a mouse model of OCA1B, but not OCA1A. Our work in the past year has focussed on three questions: 1) Does nitisinone treatment in the Himalayan (OCA1B) mouse affect retinal function? 2) Can nitisinone improve melanin pigmentation in other mouse models of OCA? and 3) Will nitisinone treatment improve pigmentation in humans with OCA1B. We have evaluated the effect of 1 month nitisinone treatment on the full-field electroretinogram (ERG) of Himalayan mice. This test evaluates overall photoreceptor- and post-photoreceptor function in the neurnal retina, as well as, to some extent, the function of the retinal pigment epithelium. It does not measure visual acuity, which is poor in mice and would not be anticipated to change with treatment. Although our analysis is ongoing, present data indicate that nitisinone does not affect any of the ERG parameters (a wave, b wave, c wave) measured. We have obtained mouse models of OCA3(brown) and OCA4(underwhite) mice. OCA3 mice have brown fur and eye color. One month of nitisinone did not result in a visible change in melanin pigmentation in these mice. Analysis of melanin-containing ocular tissues did not show any statistically different difference in melanosome number or size. OCA4 mice appear to have two distinct coat and eye colors, perhaps reminiscent of the """"""""underwhite dilute"""""""" phenotype previously described. We have performed test matings and it appears that the """"""""darker"""""""" phenotype segregates as an autosomal recessive locus that modifies the lighter phenotype. Lastly, we now have an IRB-approved study, 13-EI-0124, to study nitisinone in adults with potential OCA1B. Recruitment has begun and we will collaborate with John Chiang of the University of Oregon for molecular diagnostics. One of the complex issues addressed in our work was the development of appropriate clinical outcome measures. Since we do not anticipate that nitisinone will affect foveal function (ergo, visual acuity) in a mature (adult) retina, we are using ocular melanin pigmentation as our primary outcome variable. We have developed a semi-quantitate grading scale of iris transillumination (our primary outcome variable) and are submitting this work for publication.

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Wang, Chen; Brancusi, Flavia; Valivullah, Zaheer M et al. (2018) A novel iris transillumination grading scale allowing flexible assessment with quantitative image analysis and visual matching. Ophthalmic Genet 39:41-45
Bryan, Melanie M; Tolman, Nathanial J; Simon, Karen L et al. (2017) Clinical and molecular phenotyping of a child with Hermansky-Pudlak syndrome-7, an uncommon genetic type of HPS. Mol Genet Metab 120:378-383
Simeonov, Dimitre R; Wang, Xinjing; Wang, Chen et al. (2013) DNA variations in oculocutaneous albinism: an updated mutation list and current outstanding issues in molecular diagnostics. Hum Mutat 34:827-35
Brooks, Brian P (2011) Making progress in albinism. J AAPOS 15:1-2