Abnormal Termination of Ca <sup>2+</sup> Release Is a Common Defect of RyR2 Mutations Associated With Cardiomyopathies
Bibliographic record
Abstract
RATIONALE: Naturally occurring mutations in the cardiac ryanodine receptor (RyR2) have been associated with both cardiac arrhythmias and cardiomyopathies. It is clear that delayed afterdepolarization resulting from abnormal activation of sarcoplasmic reticulum Ca2+ release is the primary cause of RyR2-associated cardiac arrhythmias. However, the mechanism underlying RyR2-associated cardiomyopathies is completely unknown. OBJECTIVE: In the present study, we investigate the role of the NH2-terminal region of RyR2 in and the impact of a number of cardiomyopathy-associated RyR2 mutations on the termination of Ca2+ release. METHODS AND RESULTS: The 35-residue exon-3 region of RyR2 is associated with dilated cardiomyopathy. Single-cell luminal Ca2+ imaging revealed that the deletion of the first 305 NH2-terminal residues encompassing exon-3 or the deletion of exon-3 itself markedly reduced the luminal Ca2+ threshold at which Ca2+ release terminates and increased the fractional Ca2+ release. Single-cell cytosolic Ca2+ imaging also showed that both RyR2 deletions enhanced the amplitude of store overload-induced Ca2+ transients in HEK293 cells or HL-1 cardiac cells. Furthermore, the RyR2 NH2-terminal mutations, A77V, R176Q/T2504M, R420W, and L433P, which are associated with arrhythmogenic right ventricular displasia type 2, also reduced the threshold for Ca2+ release termination and increased fractional release. The RyR2 A1107M mutation associated with hypertrophic cardiomyopathy had the opposite action (i.e., increased the threshold for Ca2+ release termination and reduced fractional release). CONCLUSIONS: These results provide the first evidence that the NH2-terminal region of RyR2 is an important determinant of Ca2+ release termination, and that abnormal fractional Ca2+ release attributable to aberrant termination of Ca2+ release is a common defect in RyR2-associated cardiomyopathies.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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".