Oa1 knock-out: new insights on the pathogenesis of ocular albinism type 1

Abstract

Ocular albinism type I (OA1) is an X-linked disorder characterized by severe reduction of visual acuity, strabismus, photophobia and nystagmus. Ophthalmologic examination reveals hypopigmentation of the retina, foveal hypoplasia and iris translucency. Microscopic examination of both retinal pigment epithelium (RPE) and skin melanocytes shows the presence of large pigment granules called giant melanosomes or macromelanosomes. In this study, we have generated and characterized Oa1-deficient mice by gene targeting (KO). The KO males are viable, fertile and phenotypically indistinguishable from the wild-type littermates. Ophthalmologic examination shows hypopigmentation of the ocular fundus in mutant animals compared with wild-type. Analysis of the retinofugal pathway reveals a reduction in the size of the uncrossed pathway, demonstrating a misrouting of the optic fibres at the chiasm, as observed in OA1 patients. Microscopic examination of the RPE shows the presence of giant melanosomes comparable with those described in OA1 patients. Ultrastructural analysis of the RPE cells, suggests that the giant melanosomes may form by abnormal growth of single melanosomes, rather than the fusion of several, shedding light on the pathogenesis of ocular albinism.

Ocular Albinism Type 1: More Than Meets The Eye

“…Comparable to the MMGs described in OA1 patients, histological analysis of the RPE from mice with targeted deletion of the Oa1 gene also reveal the present of MMGs (26). During embryonic development, MMGs are not detectable in the RPE of mutant mice, but as the newborn mice mature to 7 days post-partum, a majority of the melanosomes displayed a giant phenotype, even though the number of melanosomes per cell is reportedly constant (26).…”

“…During embryonic development, MMGs are not detectable in the RPE of mutant mice, but as the newborn mice mature to 7 days post-partum, a majority of the melanosomes displayed a giant phenotype, even though the number of melanosomes per cell is reportedly constant (26). Ultrastructural analysis of the RPE in mutant Oa1 mice allowed the identification of a central core region suggestive of the structure of a normal melanosome.…”

Modifying skin pigmentation – approaches through intrinsic biochemistry and exogenous agents

“…Proteasomal degradation of TYR is characteristic for oculocutaneous albinism (OCA) type 1 (TYR) and OCA3 (TYRP1), while OCA2 (P) and OCA4 (MATP) lead to disrupted sorting of functional TYR to melanosomes. Ocular albinism type 1 (OA1) causes a disruption of melanin synthesis, primarily in the eye, by an as yet unknown mechanism [27].…”

A novel splicing site mutation of the GPR143 gene in a Chinese X-linked ocular albinism pedigree

“…d 'Addio et al (2000) expressed 19 GPR143 mutations in COS-7 cells, and most caused intracellular transport problems. GPR143-knockout mice showed hypopigmentation of the ocular fundus and giant melanosomes in the retinal pigment epithelium (Incerti et al, 2000). Lopez et al (2008) found that L-dopa was an endogenous ligand of GPR143.…”