Environmental Light Has an Essential Effect on the Disease Expression in a Dominant RPE65 Mutation

Abstract

The retina pigmented epithelium 65 kDa protein (RPE65) is an essential enzyme in the visual cycle that regenerates the 11-cis-retinal chromophore obligatory for vision. Mutations in RPE65 are associated with blinding diseases. D477G (C.1430G > A) is the only known RPE65 variant to cause autosomal dominant retinitis pigmentosa (adRP). Previously, we reported that the heterozygous D477G knock-in (WT/KI) mice exposed to dim light intensity demonstrated delayed chromophore regeneration rates and slowed recovery of photoreceptor sensitivity following photobleaching. However, visual function and retinal architecture were indistinguishable from the wild-type (WT) mice. In this study, when maintained under the physiological day-light intensity (2 K lux), the WT/KI heterozygous mice displayed retina degeneration and reduced electroretinography (ERG) amplitude, recapitulating that observed in human patients. Our findings indicated the importance of the light environment in the mechanism of RPE65 D477G pathogenicity.

Keywords: Blindness; D477G; Inherited retinopathy; Luminance; RPE65; Retinitis pigmentosa; Visual cycle.