Abstract 13579: <i>TAX1BP3</i> -Encoding TAX1-Binding Protein 3 is a Novel Genetic Cause of Autosomal Recessive Arrhythmogenic Cardiomyopathy and Causes Pro-Arrhythmic Ryanodine Receptor 2-Mediated Calcium Leak
Bibliographic record
Abstract
Introduction: Arrhythmogenic cardiomyopathy (AC) is a heart muscle disease where fibrofatty tissue replaces healthy myocardium. AC predisposes to ventricular arrhythmias and sudden cardiac death. We identified biallelic variants in the TAX1BP3- encoded tax1-binding protein 3 (TAX1BP3) in a genetically elusive family with AC. TAX1BP3 has putative roles in canonical Wnt signaling, but its function in the heart is unknown. Our goal is to identify novel mechanisms of AC development to develop therapeutics to mitigate or reverse disease progression. Hypothesis: We hypothesize that genetic loss of TAX1BP3 suppresses normal canonical Wnt-signaling in the heart, allowing pathologic remodeling and arrhythmogenesis associated with AC development. Methods: Whole exome sequencing of an AC genotype-negative family was performed. Induced pluripotent stem cells generated from peripheral blood mononuclear cells (PBMCs) from were differentiated into cardiac myocytes (iPSC-CMs) for 3 kindred. Line scans using CAL-520-labeled calcium were conducted with a Zeiss confocal microscope to capture calcium sparks after pacing iPSC-CMs. Sarcoplasmic reticulum store was measured after adding 10mM caffeine to iPSC-CMs. Adipogenesis in iPSC-CMs was visualized by immunofluorescence with Nile Red stain. Results: TAX1BP3 M78T/del variant co-segregates with AC in an autosomal recessive inheritance mode in an AC genotype-negative family. TAX1BP3 M78T/del PBMCs had reduced proliferation and qPCR from whole blood identified decreased canonical Wnt signaling. iPSC-CMs M78T/del have decreased intracellular calcium store, increased adipogenesis, and increased calcium leak associated with spontaneous calcium release events. Small molecule Wnt-activator BML-284 normalized calcium leak in iPSC-CMs M78T/del . Conclusions: Our results demonstrate that loss-of-function of TAX1BP3 is pro-arrhythmic and driven by calcium leak in iPSC-CMs which can be rescued by Wnt activation. We identified a new AC-associated gene, TAX1BP3, that has not been studied in the heart. Further studies are needed to explore the impact of TAX1BP3 on cardiac Wnt signaling, but our findings implicate Wnt activation as a possible treatment for AC - currently an untreatable, deadly disease.
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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) | 0.001 | 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 | 0.001 |
| 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".