title: Nitisinone improves eye and skin  pigmentation defects in a mouse model  of oculocutaneous albinism.
abstract: Mutation of the tyrosinase gene (TYR) causes oculocutaneous albinism, type 1 (OCA1), a condition characterized by reduced skin and eye melanin pigmentation and by vision loss. The retinal pigment epithelium influences postnatal visual development. Therefore, increasing ocular pigmentation in patients with OCA1 might enhance visual function. There are 2 forms of OCA1, OCA-1A and OCA-1B. Individuals with the former lack functional tyrosinase and therefore lack melanin, while individuals with the latter produce some melanin. We hypothesized that increasing plasma tyrosine concentrations using nitisinone, an FDA-approved inhibitor of tyrosine degradation, could stabilize tyrosinase and improve pigmentation in individuals with OCA1. Here, we tested this hypothesis in mice homozygous for either the Tyrc-2J null allele or the Tyrc-h allele, which model OCA-1A and OCA-1B, respectively. Only nitisinone-treated Tyrc-h/c-h mice manifested increased pigmentation in their fur and irides and had more pigmented melanosomes. High levels of tyrosine improved the stability and enzymatic function of the Tyrc-h protein and also increased overall melanin levels in melanocytes from a human with OCA-1B. These results suggest that the use of nitisinone in OCA-1B patients could improve their pigmentation and potentially ameliorate vision loss.
authors.affiliation: Unit on Pediatric, Developmental, and Genetic Eye Disease, National Eye Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Ighovie F
authors.initials: IF
authors.lastname: Onojafe
authors.forename: David R
authors.initials: DR
authors.lastname: Adams
authors.forename: Dimitre R
authors.initials: DR
authors.lastname: Simeonov
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chan
authors.forename: Isa M
authors.initials: IM
authors.lastname: Bernardini
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Sergeev
authors.forename: Monika B
authors.initials: MB
authors.lastname: Dolinska
authors.forename: Ramakrishna P
authors.initials: RP
authors.lastname: Alur
authors.forename: Murray H
authors.initials: MH
authors.lastname: Brilliant
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.forename: Brian P
authors.initials: BP
authors.lastname: Brooks
mesh_terms: D016115:Albinism, Oculocutaneous / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D003512:Cyclohexanones / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004795:Enzyme Stability / Q000187:drug effects / Q000235:genetics; D005127:Eye Color / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D005260:Female; D006801:Humans; D008543:Melanins / Q000378:metabolism; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D014442:Monophenol Monooxygenase / Q000737:chemistry / Q000172:deficiency / Q000235:genetics; D009154:Mutation; D009579:Nitrobenzoates / Q000627:therapeutic use*; D011247:Pregnancy; D012880:Skin Pigmentation / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism
chemical_list: D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D008543:Melanins; D009579:Nitrobenzoates; D014443:Tyrosine; D014442:Monophenol Monooxygenase; C077073:nitisinone