AbstractMutations in KCNJ13 are associated with two retinal disorders; Leber congenital amaurosis (LCA) and snowflake vitreoretinal degeneration (SVD). We examined the retina of kcnj13 mutant zebrafish (obelix^td15, c.502T > C p.[Phe168Leu]) to provide new insights into the pathophysiology underlying these conditions. Detailed phenotyping of obelix^td15 fish revealed a late onset retinal degeneration at 12 months. Electron microscopy of the obelix^td15 retinal pigment epithelium (RPE) uncovered reduced phagosome clearance and increased mitochondrial number and size prior any signs of retinal degeneration. Melanosome distribution was also affected in dark-adapted 12-month obelix^td15 fish. At 6 and 12 months, ATP levels were found to be reduced along with increased expression of glial fibrillary acidic protein and heat shock protein 60. Quantitative RT-PCR of polg2, fis1, opa1, sod1/2 and bcl2a from isolated retina showed expression changes consistent with altered mitochondrial activity and retinal stress. We propose that the retinal disease in this model is primarily a failure of phagosome physiology with a secondary mitochondrial dysfunction. Our findings suggest that alterations in the RPE and photoreceptor cellular organelles may contribute to KCNJ13-related retinal degeneration and provide a therapeutic target.