New views on RPE65 deficiency:: the rod system is the source of vision in a mouse model of Leber congenital amaurosis

Leber congenital amaurosis (LCA) is the most serious form of the autosomal recessive childhood-onset retinal dystrophies. Mutations in the gene encoding RPE65, a protein vital for regeneration of the visual pigment rhodopsin in the retinal pigment epithelium(1), account for 10-15% of LCA cases(2,3). Whereas previous studies of RPE65 deficiency in both animal models(1,4) and patients(5,6) attributed remaining visual function to cones, we show here that light-evoked retinal responses in fact originate from rods. For this purpose, we selectively impaired either rod or cone function in Rpe65(-/-) mice by generating double-mutant mice with models of pure cone function(7) (rhodopsin-deficient mice; Rho(-/-)) and pure rod function, (cyclic nucleotide-gated channel alpha3-deficient mice; Cnga3(-/-)). The electroretinograms (ERGs) of Rpe65(-/-) and Rpe65(-/-)Cnga3(-/-) mice were almost identical, whereas there was no assessable response in Rpe65(-/-)Rho(-/-) mice. Thus, we conclude that the rod system is the source of vision in RPE65 deficiency. Furthermore, we found that lack of RPE65 enables rods to mimic cone function by responding under normally cone-isolating lighting conditions. We propose as a mechanism decreased rod sensitivity due to a reduction in rhodopsin content to less than 1%. In general, the dissection of pathophysiological processes in animal models through the introduction of additional, selective mutations is a promising concept in functional genetics.