Informed reasoning: repositioning of nitisinone to treat oculocutaneous albinism Prashiela Manga, Seth J. Orlow J Clin Invest. 2011;121(10):3828-3831. https://doi.org/10.1172/JCI59763. Commentary Oculocutaneous albinism (OCA) is a group of genetic disorders characterized by hypopigmentation of the skin, hair, and eyes. Affected individuals experience reduced visual acuity and substantially increased skin cancer risk. There are four major types of OCA (OCA1–OCA4) that result from disruption in production of melanin from tyrosine. Current treatment options for individuals with OCA are limited to attempts to correct visual problems and counseling to promote use of sun protective measures. However, Onojafe et al., reporting in this issue of the JCI, provide hope for a new treatment approach for OCA, as they demonstrate that treating mice that model OCA-1b with nitisinone, which is FDA approved for treating hereditary tyrosinemia type 1, elevates plasma tyrosine levels, and increases eye and hair pigmentation. Find the latest version: https://jci.me/59763/pdf commentaries Informed reasoning: repositioning of nitisinone to treat oculocutaneous albinism Prashiela Manga and Seth J. Orlow Ronald O. Perelman Department of Dermatology and Department of Cell Biology, New York University School of Medicine, New York, New York, USA. Oculocutaneous albinism (OCA) is a group of genetic disorders characterized Melanin synthesis and its disruption by hypopigmentation of the skin, hair, and eyes. Affected individuals experi- in OCA ence reduced visual acuity and substantially increased skin cancer risk. There Tyrosinase, a type I membrane protein, are four major types of OCA (OCA1–OCA4) that result from disruption in catalyzes the first and rate-limiting reac- production of melanin from tyrosine. Current treatment options for individ- tion during melanin synthesis. Unlike many uals with OCA are limited to attempts to correct visual problems and coun- membrane proteins that exit the ER rapidly, seling to promote use of sun protective measures. However, Onojafe et al., tyrosinase is retained for an unusually long reporting in this issue of the JCI, provide hope for a new treatment approach period prior to transport to the Golgi, which for OCA, as they demonstrate that treating mice that model OCA-1b with suggests that it undergoes highly regulated/ nitisinone, which is FDA approved for treating hereditary tyrosinemia type 1, complex early processing. Maturation of elevates plasma tyrosine levels, and increases eye and hair pigmentation. tyrosinase begins during translation, when the peptide is inserted into the ER mem- Oculocutaneous albinism dence of OCA4 is not known; however, it brane by Sec61, then bound by the folding Melanin is a biopolymer synthesized from appears to be more prevalent in Japanese chaperone BiP (also known as HSPA5) (Fig- tyrosine. Upon synthesis, it is deposited in populations (7). ure 1). Additional chaperones — calnexin, specialized organelles (melanosomes) in OCAs are characterized by decreased or then calreticulin — subsequently bind the neural crest–derived melanocytes found absent melanin in skin, hair, and eyes. In peptide to facilitate glycosylation. The fol- in the skin, hair follicles, iris, uveal tract, skin, melanin plays a central role in pro- dase ER protein 57 (ERp57) is also recruited and inner ear as well as in retinal pig- tection from UV-induced carcinogenesis. to the complex to catalyze disulfide bond mented epithelium (RPE) derived from Thus, individuals with OCA are highly formation after signal sequence cleavage. the optic cup. Oculocutaneous albinism susceptible to skin cancers, particularly The processed peptide is then subject to the (OCA) denotes a group of common auto- squamous cell carcinoma. During embryo- ER quality control system that ensures that somal-recessive disorders that result from genesis, melanin synthesis in the RPE only correctly folded proteins exit the ER. disruption of melanin synthesis. There are affects development of the fovea and of Correctly folded tyrosinase is transported to four major forms: OCA1, which is caused adjacent retinal ganglion cells, which in the Golgi, where it undergoes additional gly- by mutations in the tyrosinase gene (TYR) turn regulate decussation of the nerve con- cosylation. Misfolded tyrosinase is retained (1); OCA2, caused by mutations in OCA2 necting the retina to brain at the optic chi- in the ER, undergoing cycles of folding and (2); OCA3, caused by mutations in the asm. Numerous structural abnormalities unfolding, until it is eventually targeted for tyrosinase-related protein 1 gene (TYRP1) ensue if melanogenesis is deficient. In the proteasomal degradation (10). (3); and OCA4, caused by mutations in the adult eye, melanin appears important for Many OCA1-causing TYR mutations solute carrier family 45, member 2 gene reducing light scatter and aiding acuity. result in a protein that fails to fold and (SLC45A2) (4). OCA1 affects approximate- Individuals with OCA consequently suffer is therefore unable to exit the ER (11). ly 1 in 40,000 people worldwide and is the from nystagmus, strabismus, photophobia, Tyrosinase is also retained in the ER, due to most prevalent form of OCA among indi- and loss of visual acuity that can be severe unknown mechanisms, in OCA2 (12) and viduals of mixed European descent. OCA2 enough to render them legally blind (8). OCA3 (13), whereas in OCA4, tyrosinase affects 1 in 39,000 such individuals, with The highly visible OCA phenotype — exits the ER but is not correctly transported substantially higher prevalence in African- most dramatic in individuals with OCA1, to the melanosome (14). We have previously American and Amerindian populations. who have white hair, very pale skin, and demonstrated that ER retention of tyrosi- The carrier rate of a pathogenic deletion light-colored irides — is a source of sig- nase activates the unfolded protein response of OCA2 in African-American newborns is nificant emotional and psychological (UPR) (15), a highly conserved cell signaling estimated to be 1 in 235 (5); rates in some stress. Visual insufficiencies are often cascade that increases the capacity of a cell Amerindian populations reach 1 in 200 misinterpreted as intellectual deficits in to process misfolded proteins but can lead (6). OCA3 is rare, with notable frequency affected individuals, exacerbating feel- to apoptosis if ER stress is sustained. only in African populations (3). The inci- ings of alienation. A study of Nigerians The precise functions of the remaining with OCA2 found that they experienced OCA-related proteins (excepting tyrosi- Conflict of interest: In the past year, Seth J. Orlow alienation, avoided social interactions, nase) remain unclear. We have proposed served as a consultant to Astellas Pharmaceuticals, and were less emotionally stable. Further- that OCA2 mediates glutathione transport Bristol Myers Squibb, Galderma, Glaxo Smith Kline, Provectus Pharmaceuticals, and SkinMedica. more, affected individuals were less likely into the ER to promote disulfide bond Citation for this article: J Clin Invest. 2011; to complete schooling, find employment, formation during tyrosinase maturation 121(10):3828–3831. doi:10.1172/JCI59763. and find partners (9). (16) and that TYRP1 stabilizes tyrosinase 3828 The Journal of Clinical Investigation http://www.jci.org Volume 121 Number 10 October 2011 commentaries Figure 1 Synthesis and ER-based maturation of tyrosinase. Tyrosinase is synthesized on ribosomes and translocated into the ER membrane. (i) Tyrosi- nase is bound by the chaperones BiP, then calnexin (CNX), followed by ERp57 (ii) and calreticulin (CRT). Each chaperone is required to facilitate tyrosinase folding and glycosylation. In order to fold the peptide, protein disulfide isomerases (PDIs) such as ERp57 catalyze the formation of disulfide bonds. (iii) ERp57 is converted to a reduced state during catalysis. In order to recycle the protein, the ER oxidoreductin Ero1 oxidizes the PDI, generating ROS in the process. These ROS are detoxified by reduced glutathione (GSH), which is transported into the ER from the cytosol through a channel. Based on our studies (16), we hypothesize that the OCA2 protein serves as a GSH pump. (iv) ERp57 then catalyzes the isomerization of disulfide bonds to form a folded peptide. Correctly folded tyrosinase is released by the chaperones and then (v) recruited to a vesicle for transport to the Golgi. Recruitment may be facilitated by OCA2 and TYRP1. (vi) In the event that the protein is misfolded, disulfide bonds are removed by PDIs, which generates ROS that are removed by GSH, and tyrosinase is refolded. There are a limited number of protein refolding cycles, after which tyrosinase is transported to and degraded by proteasomes. GSSG, oxidized glutathione. (17). Costin et al. have proposed a role for TYR mutations can be improved by cultur- the melanocytes at the epidermal basal layer. the OCA4 protein, SLC45A2, in transport ing cells at temperatures of approximately Tyrosinase processing in cultured melano- of tyrosinase from Golgi to melanosomes, 31°C (11). In the early 1960s, long before cytes can be greatly improved by tyrosine, given that mutations in the SLC45A2 locus the tyrosinase-encoding gene was identi- DOPA (which is a cofactor for tyrosinase), result in trafficking of functional tyrosi- fied, researchers found that hair bulbs from and a variety of pH-altering agents, includ- nase to the plasma membrane (14). individuals with what we now call OCA-1A ing monensin