Correlating the Expression and Functional Activity of ABCA4 Disease Variants With the Phenotype of Patients With Stargardt Disease
Bibliographic record
Abstract
Purpose: Stargardt disease (STGD1), the most common early-onset recessive macular degeneration, is caused by mutations in the gene encoding the ATP-binding cassette transporter ABCA4. Although extensive genetic studies have identified more than 1000 mutations that cause STGD1 and related ABCA4-associated diseases, few studies have investigated the extent to which mutations affect the biochemical properties of ABCA4. The purpose of this study was to correlate the expression and functional activities of missense mutations in ABCA4 identified in a cohort of Canadian patients with their clinical phenotype. Methods: Eleven patients from British Columbia were diagnosed with STGD1. The exons and exon-intron boundaries were sequenced to identify potential pathologic mutations in ABCA4. Missense mutations were expressed in HEK293T cells and their level of expression, retinoid substrate binding properties, and ATPase activities were measured and correlated with the phenotype of the STGD1 patients. Results: Of the 11 STGD1 patients analyzed, 7 patients had two mutations in ABCA4, 3 patients had one detected mutation, and 1 patient had no mutations in the exons and flanking regions. Included in this cohort of patients was a severely affected 11-year-old child who was homozygous for the novel p.Ala1794Pro mutation. Expression and functional analysis of this variant and other disease-associated variants compared favorably with the phenotypes of this cohort of STGD1 patients. Conclusions: Although many factors contribute to the phenotype of STGD1 patients, the expression and residual activity of ABCA4 mutants play a major role in determining the disease severity of STGD1 patients.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 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".