LIGHT-INDUCED ACCELERATION OF PHOTORECEPTOR DEGENERATION IN TRANSGENIC MICE EXPRESSING MUTANT RHODOPSIN

Purpose. Mutations at various loci on the rhodopsin gene have been sho wn to cause autosomal dominant retinitis pigmentosa (ADRP). One of the most common is a point mutation (P23H) near the N-terminus of the pro tein. The authors have studied the effects of light deprivation on the rate of degeneration in pigmented transgenic mice expressing the P23H mutation as well as two additional mutations near the N-terminus of o psin (V20G, P27L). Methods, Transgenic and normal littermates were rea red in darkness or in cyclic light (similar to 7 foot-candle) for peri ods of 2, 4, or 6 months. Retinal structure and function were evaluate d by electroretinography, retinal densitometry, light microscopy, and TUNEL labeling. Results. Retinas of normal animals, whether reared in darkness or in cyclic light, had no structural or functional abnormali ties. The rate of photoreceptor degeneration in dark-reared transgenic mice was significantly slower than in transgenic mice raised under cy clic light conditions. Differences between the two groups of animals w ere evident in the retinal histology, the electroretinographically det ermined sensitivity to photic stimulation, and the rhodopsin levels in the retina. TUNEL labeling of retinal wholemounts showed that cyclic light-reared animals had a threefold higher incidence of photoreceptor cell death than their dark-reared counterparts; the density of apopto tic cells was greatest in the inferior retina, the region most severel y affected in patients with the P23H mutation. In comparison, photorec eptor cell death was more uniformly distributed across the retina in d ark-reared transgenic mice. Conclusions, These findings suggest that l ight activation of rhodopsin contributes to the severity of the degene rative disease resulting from the P23H opsin mutation, and they raise the possibility that minimizing exposure to light may help to prolong useful vision of patients with this form of retinitis pigmentosa.