Inhibition of Ca <sup>2+</sup> channel surface expression by mutant bestrophin‐1 in RPE cells
Bibliographic record
Abstract
Abstract The BEST1 gene product bestrophin‐1, a Ca 2+ ‐dependent anion channel, interacts with Ca V 1.3 Ca 2+ channels in the retinal pigment epithelium (RPE). BEST1 mutations lead to Best vitelliform macular dystrophy. A common functional defect of these mutations is reduced trafficking of bestrophin‐1 into the plasma membrane. We hypothesized that this defect affects the interaction partner Ca V 1.3 channel affecting Ca 2+ signaling and altered RPE function. Thus, we investigated the protein interaction between Ca V 1.3 channels and bestrophin‐1 by immunoprecipitation, Ca V 1.3 activity in the presence of mutant bestrophin‐1 and intracellular trafficking of the interaction partners in confluent RPE monolayers. We selected four BEST1 mutations, each representing one mutational hotspot of the disease: T6P, F80L, R218C, and F305S. Heterologously expressed L‐type channels and mutant bestrophin‐1 showed reduced interaction, reduced Ca V 1.3 channel activity, and changes in surface expression. Transfection of polarized RPE (porcine primary cells, iPSC‐RPE) that endogenously express Ca V 1.3 and wild‐type bestrophin‐1, with mutant bestrophin‐1 confirmed reduction of Ca V 1.3 surface expression. For the four selected BEST1 mutations, presence of mutant bestrophin‐1 led to reduced Ca V 1.3 activity by modulating pore‐function or decreasing surface expression. Reduced Ca V 1.3 activity might open new ways to understand symptoms of Best vitelliform macular dystrophy such as reduced electro‐oculogram, lipofuscin accumulation, and vision impairment.
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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".