Pathogenic Mechanisms Underlying Stargardt Macular Degeneration Linked to Mutations in the Transmembrane Domains of ABCA4
Bibliographic record
Abstract
Abstract ABCA4 is an ATP-binding cassette (ABC) transporter predominantly expressed in photoreceptors where it transports the substrate N-retinylidene-phosphatidylethanolamine across disc membranes thereby facilitating the clearance of retinal compounds from photoreceptor outer segments. Loss of function mutations in ABCA4 cause the accumulation of bisretinoids leading to Stargardt disease (STGD1) and other retinopathies. In this study, we examined the expression and functional properties of ABCA4 harboring disease-causing missense mutations in the two transmembrane domains (TMDs) of ABCA4. Our results indicate that these mutations lead to protein misfolding, loss in substrate binding, decreased ATPase activity or a combination of these properties. Additionally, we identified an arginine (R653) in transmembrane segment 2 of ABCA4 as a residue essential for substrate binding and substrate-stimulated ATPase activity. The expression and functional activity of the TMD variants correlate well with the severity of STGD1. Our studies provide a basis for developing and evaluating novel treatments for STGD1.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 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 teacher head, 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".