Functional validation of the Nav1.5/R1432G Brugada syndrome variant using a Nav1.5 knockout iPSC-derived cardiomyocyte model
Bibliographic record
Abstract
Brugada syndrome is a rare inherited cardiac arrhythmia disorder primarily characterized by ventricular fibrillation, which can lead to sudden cardiac death. It follows an autosomal dominant pattern of inheritance and is most associated with dysfunction of the cardiac sodium channel Nav1.5. A novel and physiologically relevant approach to studying Nav1.5 variants involves the use of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes lacking endogenous Nav1.5 expression (Nav1.5 KO). This model allows for precise evaluation of variant-specific effects in a human cardiac cellular context. In this study, we investigated the Nav1.5/R1432G variant, which was previously identified in a patient diagnosed with Brugada syndrome. Sodium currents were recorded using the patch clamp technique in a whole-cell configuration. The Nav1.5/WT channel and the Nav1.5/R1432G variant were labeled by immunocytochemistry. Our results revealed a clear loss-of-function phenotype, consistent with Brugada syndrome. Furthermore, immunocytochemistry demonstrated a significant defect in membrane trafficking of the R1432G variant, supporting the hypothesis that impaired channel surface expression underlies its functional deficit. Action potential analysis revealed a marked reduction in the ventricular depolarization rate, consistent with impaired sodium channel function.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".