To elucidate the molecular mechanisms underlying the light-sensitive
retinal degeneration caused by the
rhodopsin mutation P23H, which causes
retinitis pigmentosa (RP) in humans, we expressed Xenopus laevis, bovine, human, and murine forms of P23H
rhodopsin in transgenic X. laevis rod photoreceptors. All P23H
rhodopsins caused aggressive
retinal degeneration associated with low expression levels and retention of P23H
rhodopsin in the endoplasmic reticulum (ER), suggesting involvement of
protein misfolding and ER stress. However,
light sensitivity varied dramatically between these RP models, with complete or partial rescue by dark rearing in the case of bovine and human P23H
rhodopsin, and no rescue for X. laevis P23H
rhodopsin. Rescue by dark rearing required an intact
11-cis-retinal chromophore binding site within the
mutant protein and was associated with truncation of the P23H
rhodopsin N terminus. This yielded an abundant nontoxic approximately 27 kDa form that escaped the ER and was transported to the rod outer segment. The truncated
protein was produced in the greatest quantities in dark-reared retinas expressing bovine P23H
rhodopsin and was not observed with X. laevis P23H
rhodopsin. These results are consistent with a mechanism involving enhanced protein folding in the presence of
11-cis-retinal chromophore, with ER exit assisted by proteolytic truncation of the N terminus. This study provides a molecular mechanism for
light sensitivity observed in other transgenic models of RP and for phenotypic variation among RP patients.