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, 59 (12), 4945-4952

Minimal Efficacy of Nitisinone Treatment in a Novel Mouse Model of Oculocutaneous Albinism, Type 3

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Minimal Efficacy of Nitisinone Treatment in a Novel Mouse Model of Oculocutaneous Albinism, Type 3

Ighovie F Onojafe et al. Invest Ophthalmol Vis Sci.

Abstract

Purpose: Oral nitisinone has been shown to increase fur and ocular pigmentation in a mouse model of oculocutaneous albinism (OCA) due to hypomorphic mutations in tyrosinase (TYR), OCA1B. This study determines if nitisinone can improve ocular and/or fur pigmentation in a mouse model of OCA type 3 (OCA3), caused by mutation of the tyrosinase-related protein 1 (Tyrp1) gene.

Methods: Mice homozygous for a null allele in the Tyrp1 gene (C57BL/6J-Tyrp1 b-J/J) were treated with 8 mg/kg nitisinone or vehicle every other day by oral gavage. Changes in fur and ocular melanin pigmentation were monitored. Mature ocular melanosome number and size were quantified in pigmented ocular structures by electron microscopy.

Results: C57BL/6J-Tyrp1 b-J/J mice carry a novel c.403T>A; 404delG mutation in Tyrp1, predicted to result in premature truncation of the TYRP1 protein. Nitisinone treatment resulted in an approximately 7-fold increase in plasma tyrosine concentrations without overt toxicity. After 1 month of treatment, no change in the color of fur or pigmented ocular structures was observed. The distribution of melanosome cross-sectional area was unchanged in ocular tissues. There was no significant difference in the number of pigmented melanosomes in the RPE/choroid of nitisinone-treated and control groups. However, there was a significant difference in the number of pigmented melanosomes in the iris.

Conclusions: Treatment of a mouse model of OCA3 with oral nitisinone did not have a favorable clinical effect on melanin production and minimally affected the number of pigmented melanosomes in the iris stroma. As such, treatment of OCA3 patients with nitisinone is unlikely to be therapeutic.

Figures

Figure 1
Figure 1
Novel Tyrp1 mutation in C57BL/6J-Tyrp1b-J/J mice. DNA sequencing detected c.403T>A; 404delG (p.A68stop) mutation, predicted to result in premature truncation (A). Western blot of protein lysates from whole eyes of control C57BL/6J mice (Tyrp1 wild-type allele), BALB/cJ and DBA/2J (Tyrp1b/b allele), and OCA3 (Tyrp1b-J/b-J allele) mutants (B). A 70-kDa, presumably glycosylated, band was detected in control, BALB/cJ, and DBA/2J lanes. At 50 kDa, an additional, presumably nonglycosylated, band of variable intensity was detected only in BALB/cJ and DBA/2J b allele samples. In addition, lower molecular weight bands were visible in the DBA/2J sample. No bands were visible in the OCA3 lane. Schematic representation of Tyrp1 b-J and b alleles (C). Color coat of parent and offspring from crossing of OCA3 with BALB/cJ and DBA/2J mutants (D).
Figure 2
Figure 2
Treatment of mice with 8 mg/kg oral nitisinone for 1 month did not visibly increase fur (A, B), iris (C, D), or fundus (E, F) pigmentation. The dotted lines in (A) and (B) outline the patch of fur that was shaved, as pigment is preferentially deposited in actively growing fur.
Figure 3
Figure 3
Electron micrographs of the melanin-containing ocular structures. RPE (A, D), choroid (B, E), and iris (C, F) are shown.
Figure 4
Figure 4
Quantification of the number of pigmented melanosomes in the iris, choroid, and RPE of treated (n = 7) and control C57BL/6J-Tyrp1b-J/J mice (n = 7). In the iris, there was a statistically significant increase in the number of pigmented melanosomes, two-tailed t-test P < 0.01. Error bars represent ± SD.
Figure 5
Figure 5
Distribution of melanosome cross-sectional area in treated and control C57BL/6J-Tyrp1b-J/J mice. There was no significant difference between the two groups, although melanosomes from the untreated mice covered a larger size range.

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