DISSECTING THE MOLECULAR BASIS OF OCULAR ALBINISM TYPE 1: ENLIGHTENING SIGNAL TRANSDUCTION IN THE ENDOMEMBRANE SYSTEM

Ocular albinism type 1 is an X-linked inherited disorder, with affected males showing severe visual defects, and carrier females displaying only minor signs of the disorder. The disease affects melanin-producing pigment cells of the skin and eyes, which are responsible for the color of the hair, eyes and skin. In particular, patients with ocular albinism display characteristic abnormalities of the intracellular organelles where melanin is stored, named melanosomes, which become giant and are therefore defined macromelanosomes. The protein product of the ocular albinism gene, named OA1, is a pigment cell-specific membrane glycoprotein, displaying structural and functional features of G protein-coupled receptors (GPCRs). However, in contrast to canonical GPCRs, OA1 is not localized to the cell membrane, but is targeted to the melanosomal membrane, where it is supposed to sense and regulate maturation and growth. Our proposal is aimed at studying the pathogenesis of ocular albinism by the identification of the molecular mechanisms by which OA1 accomplish its function. These studies will allow us to obtain fundamental information to plan a future correction of the defect by genetic or pharmacological therapies. Furthermore, OA1 represent the first example of an exclusively intracellular GPCR, supporting the hypothesis that signaling systems mediated by GPCRs might also operate at the internal membranes. Therefore, the study of ocular albinism represents an interesting model for biological and biomedical research in general, since it might provide us with information on the signaling mechanisms operating not only on the melanosomes, but also on other intracellular organelles performing essential functions within the body.