Invest Ophthalmol Vis Sci 2025 Dec 01;6615:9. doi: 10.1167/iovs.66.15.9.

A Survey of Opsin Localization, Glycosylation, and Light/Chromophore Influence on Degeneration in 26 Rhodopsin-Associated RP Models.

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PURPOSE: Mutations in rhodopsin (RHO) cause autosomal-dominant RP, which has multiple clinical subclasses, including class B1 ("sector") RP in which the asymmetric retinal degeneration (RD) suggests an environmental influence. The pathogenic mechanisms of most class B1 mutations are uncharacterized. We generated new animal models of RHO-associated RP to examine RHO expression, localization, glycosylation, and the influence of light and chromophore binding on RD. METHODS: We generated transgenic Xenopus laevis expressing wild-type or mutant human RHO transgenes. Confocal images were used to evaluate RD and trafficking. Immunoassays were used to quantify RD and investigate RHO glycosylation. RESULTS: We created X. laevis models of 26 different forms of RHO-associated RP. Most mutations caused RD, with the exception of those at residues F45, G101, and R135. Many variants did not alter RHO localization. Multiple class B1-associated RHO mutants induced light-dependent RD, suggesting light is the environmental influence associated with the class B1 phenotype. However, the degeneration associated with two partially endoplasmic reticulum-retained class B1 mutants (S22R and D190G) was not mitigated by dark rearing. P23H and S176F constituted a distinct subclass associated with inner segment retention and proteolytic cleavage. CONCLUSIONS: Many RHO mutations do not substantially alter RHO localization or glycosylation. The exceptions we identified are P23H and S176F, which dramatically mislocalize, and constitute a distinct category of proteolytically cleaved misfolding variants. L31Q and T58R induce RD by mechanisms similar to glycosylation-deficient variants, despite the lack of glycosylation defects. Intermediate phenotypes indicate at least one previously undescribed mechanism for class B1 RP pathogenesis.

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