Abstract Fri083: A Cardiac Ryanodine Receptor C-terminal Truncation Causes Calcium Release Deficiency Syndrome, but not Catecholaminergic Polymorphic Ventricular Tachycardia
Bibliographic record
Abstract
The cardiac ryanodine receptor (RyR2) controls the release of Ca 2+ from the sarcoplasmic reticulum (SR) and plays an essential role in excitation-contraction coupling in cardiomyocytes. Defective RyR2 function because of naturally occurring RyR2 variants can cause cardiac arrhythmias, cardiomyopathies, and sudden cardiac death (SCD). Gain-of-function (GOF) missense variants in the cardiac RyR2 are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), which has been extensively characterized. Our team found that RyR2 loss-of-function (LOF) variants can cause a new entity of cardiac channelopathy, which is termed Ca 2+ release deficiency syndrome (CRDS). CRDS is characterized by ventricular arrhythmias (VAs) and SCD, but a normal exercise stress testing (EST). Recently, a RyR2 C-terminal truncating variant, R4790Ter, was reported in a patient presenting with unexplained cardiac arrest. In vitro studies using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) showed that the RyR2-R4790Ter nonsense variant behaves like RyR2-GOF variants that are often associated with CPVT. However, it is unknown how a RyR2 C-terminal truncation that results in loss of channel function could lead to GOF phenotypes. Therefore, we have two aims for this project, 1) To identify and functionally characterize CRDS associated RyR2 LOF variants in HEK293 cells; 2) To understand mechanisms of CRDS associated with RyR2 nonsense truncating variants. The RyR2 truncating variants, including the R4790Ter, were generated by using the overlap extension method with PCR. We also generated a knock-in mouse model harboring the R4790Ter +/- variant to investigate the susceptibility to VAs and potential arrhythmogenic mechanisms. We found that C-terminal RyR2 truncating variants are non-functional and can exert a dominant negative impact on the RyR2 WT. Mouse model carrying the RyR2-R4790Ter +/- suppressed stress-induced VAs. On the other hand, R4790Ter +/- increased the propensity for pacing-induced VAs using the CRDS-specific stimulation protocol consisting of long-burst, long pause, and short-coupled (LBLPS) ventricular extra-stimulus. RyR2-R4790Ter +/- also promoted Ca 2+ alternans in intact hearts compared with RyR2-WT, a hallmark of RyR2-CRDS variants. Therefore, our findings indicate that RyR2 C-terminal RyR2-R4790Ter +/- truncating variant is associated with CRDS, but not CPVT.
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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 | 0.000 |
| 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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 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".