Understanding the molecular mechanisms of arrhythmogenic right ventricular cardiomyopathy caused by TMEM43 p.S358L mutation
Bibliographic record
Abstract
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiac disease characterized by fibrofatty infiltration of the myocardium, life-threatening arrhythmias, and sudden cardiac death. Newfoundland and Labrador is home to a substantial founder population with an autosomal dominant mutation in the transmembrane protein 43 (TMEM43) gene (c.1073C>T; p.S358L), responsible for ARVC type 5. Although we know that this mutation causes ARVC, there is limited information on the TMEM43 protein life cycle, protein-protein interactions, and function. Additionally, it is unknown how the p.S358L mutation affects TMEM43 function, contributes to ARVC, or why it affects only the heart despite being widely expressed. Here I investigate the intracellular trafficking of wild-type TMEM43 in human induced pluripotent stem cells (iPSCs) and iPSC-cardiomyocytes (iPSC-CMs). I find that TMEM43 resides primarily in early endosomes in iPSCs. Interestingly, although TMEM43 remains localized to early endosomes in early contracting iPSC-CMs, it shifts toward the nuclear envelope as iPSC-CMs are cultured in vitro for an extended period of time. CRISPR-Cas9 genetic ablation of the TMEM43 gene has no apparent effects on several intracellular organelles previously shown to be affected by the TMEM43-S358L mutation. However, TMEM43-/- iPSC-CMs exhibit subtle calcium handling aberrations pointing toward a pro-arrhythmic phenotype. Finally, primary ARVC patient dermal fibroblasts show significant changes in the expression of extracellular matrix proteins, which may play a role in the fibrosis seen in ARVC. Together, these studies begin to unravel the basic life cycle and function of the TMEM43 protein in a human-derived cellular model of ARVC.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.002 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| 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".