Photoreceptor ABC Transporter ABCA4: Its Role in the Visual Cycle and Retinal Degenerative Diseases

Abstract

ABCA4 is a member of the superfamily of ATP binding cassette (ABC) proteins that is localized in outer segment disc membranes of rod and cone photoreceptor cells. Mutations in the ABCA4 gene are responsible for Stargardt macular dystrophy, cone-rod dystrophy and retinitis pigmentosa. Biochemical studies together with analysis of abca4 knockout mice implicate ABCA4 in the transport of N-retinylidene-phosphatidylethanolamine across disk membranes. This transport process facilitates the complete removal of retinal derivatives from photoreceptors following the photobleaching of rhodopsin and cone opsin as part of the visual cycle. Loss in the activity of ABCA4 leads to the production of diretinal derivatives in disc membranes which accumulate in adjacent retinal pigment epithelial (RPE) cells as lipofuscin deposits following phagocytosis of outer segments. Progressive buildup of these toxic diretinal compounds causes the degeneration of RPE and photoreceptors and a loss in vision. Recently, we have investigated the effect of C-terminal deletion, including several disease related mutations, on the structural and functional properties of ABCA4. Our studies indicate that ABCA4 contains a conserved motif near the C-terminus that is crucial for proper protein folding and functional activity of ABCA4. Individuals missing this motif due to C-terminal truncation of ABCA4 exhibit a severe form of retinal degeneration known as cone-rod dystrophy.