The mouse model for ocular albinisin type 1 (OA1) as a tool to study Oa1 function in RPE development

Purpose: Ocular Albinism type 1 (OA1) is an X-linked form of albinism isolated to the eye. The disease causes a severe visual handicap in affected males, manifesting foveal hypoplasia, horizontal and rotatory nystagmus, strabismus, photophobia and lack of stereoscopic vision. Histological analysis of patient melanocytes from the RPE and the skin reveals giant melanosomes (macromelanosomes). Mutations causing this disease were identified in OA1 gene. OA1 is specifically expressed in the retinal pigment epithelium (RPE) and in skin melanocytes . The protein is localized on the melanosomal membrane and displays characteristics typical of the seven transmembrane G protein coupled receptors. In order to understand the biological function of OA1, we generated a mouse model for the disease. Methods: To generate Oa1 null mice, we deleted the first exon of Oa1 by homologous recombination in ES cells. Histological studies were performed on RPE of wild-type and mutant mice. Interactions of Oa1 with other melanosomal proteins was investigated by mating Oa1 null mice with p and c mice. Ultrastructural and biochemical analyses were conducted in double mutant mice. Results: Histological analysis of the eyes in Oa1 mutants showed that the RPE was more lightly pigmented. Abnormally large melanosomes (macromelanosomes) could be identified by electron microscopy within the RPE. Interestingly, macromelanosomes could be seen just after birth in mutant mice. Oa1 knock-out mice display a misrouting of the optic fibers as in OA1 patients. A significant decrease of ipsilateral optic fibers could be measured in Oa1 knock-out mice as found in other albino mice. To investigate the function of Oa1 on the melanosomal membrane and its interaction with other genes causing different forms of albinism, we mated Oa1 null mice with p and c mice. Ultrastructural and biochemical analyses were performed in double mutant mice, finding a correlation of the macromelanosomal phenotype and level of pigmentation. We have also studied genes regulating Oa1 expression during development (e.i. Mitf) and we have started experiments aimed to the identification of genes downstream to it. Conclusion: We developed a mouse model for OA1. Our data demonstrate that the Oa1 knock-out mouse is indeed a good model for the study of OA1 pathology. Furthermore the mouse model will be valuable for the identification of factors mediating RPE influence on retinal development.