Ocular albinism type 1 is characterized by impaired visual acuity, nystagmus, photophobia, strabismus and loss of stereoscopic vision. It is inherited as an X chromosome-linked trait. Similarly to other types of albinism, it is associated with misrouting of the optic tracts during development. The histopathological hallmark of the disease is the presence of macromelanosomes in both skin melanocytes and retinal pigment epithelium (RPE). Following identification of the OA1 gene, several loss-of-function mutations were identified in patients. However, these account for approximately 70% of the cases studied, the remaining mutations being so far undetected. The OA1 protein product shares sequence similarity with G-protein coupled receptors and binds G proteins. Unlike most members of this protein family, OA1 is intracellular, being located on the melanosomal membrane. Both the macromelanosomal phenotype and the subcellular localization of the OA1 protein suggest a defect in melanosome biogenesis in ocular albinism. However, the precise role of OA1 in this fundamental process is still unknown. An important model system to study OA1 function and disease pathogenesis is the OA1 knock-out mouse which recapitulates the human disease phenotype. The goals of this project are to: 1) identify the full spectrum of mutations causing the disease, 2) study the requirement of OA1 during visual system development and maintenance, 3) discover the pathogenetic steps leading from mutations of the OA1 gene to disease phenotype, 4) characterize the functional interaction of OA1 with other genes involved in albinism to understand their role in melanosome biogenesis, 5) develop both pre- and post- natal OA1 gene delivery approaches to the RPE of animal models, aiming at phenotype prevention and rescue, respectively. These studies will advance our understanding of OA1 function in pigmentation, RPE function, melanosome biogenesis, and optic nerve development. In addition, they will lead to a deeper understanding of the pathogenesis of ocular albinism type 1 as well as of other types of albinism. Finally, the gene delivery approaches developed may represent important tools for future treatment of eye diseases involving RPE.
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