Human RyR2 (Ryanodine Receptor 2) Loss-of-Function Mutations
Bibliographic record
Abstract
Background: The overall objective of the present study is to extend our understanding of the clinical phenotype and underlying mechanism of a newly discovered cardiac arrhythmia syndrome through a multicenter study. Gain-of-function mutations in the cardiac Ca 2+ release channel (RyR2 [ryanodine receptor 2]) cause catecholaminergic polymorphic ventricular tachycardia, whereas loss-of-function RyR2 mutations are linked to a new cardiac arrhythmia disorder termed Ca 2+ -release deficiency syndrome (CRDS). Catecholaminergic polymorphic ventricular tachycardia is an inherited arrhythmia disorder characterized by stress-induced bidirectional and polymorphic ventricular tachyarrhythmias and is routinely diagnosed by using exercise stress testing. Conversely, RyR2-CRDS is characterized by ventricular arrhythmias and sudden cardiac death but a negative exercise stress testing for catecholaminergic polymorphic ventricular tachycardia. There are currently no clinical diagnostic tests for CRDS and affected patients may manifest with sudden cardiac death as their first symptom. In the absence of effective clinical diagnostic tools, in vitro functional characterization of associated RyR2 mutations provides an alternative means to identify potential cases of CRDS. Methods: We searched for patients presenting with phenotypes compatible with CRDS that have RyR2 mutations and performed in vitro functional characterization. Results: We found that 3 novel (G570D, R4147K, and A4203V) and 2 previously reported (M4109R and A4204V) RyR2 mutations associated with CRDS phenotypes markedly reduced caffeine-induced Ca 2+ release and store overload-induced Ca 2+ release. We also characterized 2 additional loss-of-function RyR2 mutations previously reported (Q3925E and L4769S) that are located in the central and channel pore-forming domains critical for Ca 2+ activation and channel gating. Q3925E was identified through postmortem genetic testing in an individual who died suddenly, while L4769S is a variant of uncertain significance reported in ClinVar, suggesting that RyR2 CRDS may be under detected. Conclusions: These findings provide further support for the existence of an emerging RyR2 loss-of-function associated arrhythmia syndrome (CRDS) and shed new insights into the disease mechanism.
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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".