A Survey of Opsin Localization, Glycosylation, and Light/Chromophore Influence on Degeneration in 26 <i>Rhodopsin</i> -Associated RP Models
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".