Abca4, mutated in Stargardt Disease, is required for cone outer segment structural integrity.

Stargardt Disease (STGD), the leading cause of inherited childhood blindness, is primarily caused by mutations in the ABCA4 gene, yet the underlying mechanisms of photoreceptor degeneration remain elusive, partly due to limitations in existing animal disease models. To expand our understanding, we mutated the ABCA4 paralogues, abca4a and abca4b, in zebrafish, which has a cone-rich retina. Our study unveiled striking dysmorphology and elongation of cone outer segments in abca4a;abca4b double mutants, alongside reduced phagocytosis by the retinal pigmented epithelium. We report that Abca4 protein forms a distinctive stripe along the length of cone outer segments, suggesting a potential structural role. We further show that wild-type cone outer segments constitutively present externalized phosphatidylserine, an 'eat-me' signal, and this pattern is disrupted in abca4a;abca4b double mutants, potentially contributing to reduced RPE phagocytic activity. More broadly, constitutive presentation of the "eat-me" signal by cone outer segments, if conserved in humans, has important implications for other retinal degenerative diseases, including age-related macular degeneration. This zebrafish model provides novel insights into cone dysfunction and presents a promising platform for unraveling the mechanisms of STGD pathogenesis and advancing therapeutic interventions.