Investigating the Pathogenicity of <i>VSX1</i> Missense Mutations and Their Association With Corneal Disease
Bibliographic record
Abstract
Purpose: Despite numerous studies associating Visual System Homeobox 1 (VSX1), with posterior polymorphous corneal dystrophy and keratoconus, its role in these diseases is unclear. Here we examine the pathogenicity of VSX1 missense mutations in vitro and in a mouse genetic model. Methods: Vsx1 transcriptional repressor activity, protein stability, and subcellular localization activity, was examined using luciferase reporter-based assays, western blotting and immunolabeling, respectively, in transfected human embryonic kidney 293T cells. A genetic model for VSX1 p.P247R was generated to investigate pathogenicity of the mutation, in vivo. A wholemount confocal imaging approach on unfixed intact eyes was developed to examine corneal morphology, curvature, and thickness. Immunolabeling and electroretinography was used to examine retinal phenotype. Results: A mutation corresponding to human VSX1 p.P247R led to enhanced transcriptional repressor activity, in vitro. A mouse model for VSX1 p.P247R did not have any observable corneal defect, but did exhibit an abnormal electroretinogram response characterized by a more prominent ON as opposed to OFF panretinal responsiveness. In vitro analysis of additional VSX1 missense mutations showed that they either enhanced repressor activity or did not alter activity. Conclusions: Our results indicate that although VSX1 sequence variants can alter transcriptional activity, in the context of a mouse genetic model, at least one of these changes does not lead to corneal abnormalities. While we cannot exclude a role for VSX1 as a risk factor for corneal disease, on its own, it does not appear to play a major causative role.
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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) | 0.001 | 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".