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MW Seeliger, C Grimm, GB Jaissle, E Zrenner, CE Remé, P Humphries, M Biel, RN Fariss, TM Redmond, A Wenzel; Genetic Separation Of Rod And Cone-driven Activity In RPE65 Knockout Mice Identifies The Rods As The Source Of Vision In A Form Of Lebers Congenital Amaurosis . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3682.
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Purpose: Dysfunction of RPE65, a protein vital for the re-isomerization of all-trans retinol in the visual cycle, causes severe childhood blindness (Lebers congenital amaurosis, LCA). The purpose of this work was to investigate the source of vision in LCA based on RPE65-/- mice. Methods: Double knockouts (DKOs) we generated by breeding RPE65-/- mutants with models of pure cone (rhodopsin knockout mice, Rho-/-) or pure rod function (cyclic nucleotide-gated channel 3 knockout mice, CNG3-/-), to investigate rod- and cone-mediated vision. Ganzfeld electroretinograms (ERGs) were obtained from all mice using single flash and flicker stimuli under both scotopic and photopic conditions. Retinal morphology was analyzed histologically to exclude differences in development. Results: We found that the ERG of Rpe65-/- and Rpe65/Cnga3 DKO mice was almost identical, whereas there was no assessable response in Rpe65/Rho DKOs. Furthermore, we found that lack of RPE65 enables rods to mimic cone function by responding under normally cone-isolating lighting conditions. We propose as mechanism a decreased rod sensitivity due to an approximately thousandfold reduction of rhodopsin. Conclusions: Whereas previous studies on RPE65 deficiency in both animal models and patients attributed remaining visual function to cones, we show that light-evoked retinal responses in fact originate from rods. In general, the dissection of pathophysiological processes in animal models through the introduction of additional, selective mutations is a promising concept in functional genetics.
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