hERG quality control and the long QT syndrome
Bibliographic record
Abstract
Long-QT syndrome type-2 (LQT2) is characterized by reduced functional expression of the human ether-à-go-go related (hERG) gene product, resulting in impaired cardiac repolarization and predisposition to fatal arrhythmia. Previous studies have implicated abnormal trafficking of misfolded hERG as the primary mechanism of LQT2, with misfolding being caused by mutations in the hERG gene (inherited) or drug treatment (acquired). More generally, environmental and metabolic stresses present a constant challenge to the folding of proteins, including hERG, and must be countered by robust protein quality control (QC) systems. Disposal of partially unfolded yet functional plasma membrane (PM) proteins by protein QC contributes to the loss-of-function phenotype in various conformational diseases including cystic fibrosis (CF) and long-QT syndrome type-2 (LQT2). The prevalent view has been that the loss of PM expression of hERG is attributed to biosynthetic block by endoplasmic reticulum (ER) QC pathways. However, there is a growing appreciation for protein QC pathways acting at post-ER cellular compartments, which may contribute to conformational disease pathogenesis. This article will provide a background on the structure and cellular trafficking of hERG as well as inherited and acquired LQT2. We will review previous work on hERG ER QC and introduce the more novel view that there is a significant peripheral QC at the PM and peripheral cellular compartments. Particular attention is drawn to the unique role of the peripheral QC system in acquired LQT2. Understanding the QC process and players may provide targets for therapeutic intervention in dealing with LQT2.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".