Heteromeric interactions between wild-type and mutant subunits of the «ether-a-go-go» related gene (hERG) channel, in the context of the type II congenital Long QT syndrome
Bibliographic record
Abstract
Mutations in the human Ether-a-go-go-Related Gene (hERG1, or KCNH2) are linked to the type 2 congenital Long QT syndrome (LQT2), characterized by delayed ventricular repolarization and predispositions for the lethal torsade de pointes arrhythmia.hERG1 encodes subunits of the tetrameric voltage gated potassium ion channel hERG, which controls repolarization of the cardiomyocyte plasma membrane.Among the hERG LQT2 mutations, around 88% cause trafficking defects which lead to reduced cell surface channel expression and delayed repolarization.There are nearly 500 mutants found in hERG, but only a small fraction have been characterized.Patients are typically heterozygous, with the mutant allele overriding the function of the wild type (WT) allele.In multimeric channels like hERG, mutant subunits may exert a dominant negative (DN) effect by co-assembling with WT subunits and inducing degradation of the mixed tetramer.Alternatively, the mutant subunits may fail to interact with WT and be degraded as homotetramers or monomers, causing an overall shortage of functional subunits due to haploinsufficiency (HI).DN mutants are predicted to be more deleterious due to a greater suppressive effect on the WT subunits.This study explores the molecular mechanism of several hERG trafficking deficient mutants by detecting and distinguishing DN and HI effects.It also serves as a first step towards predicting severity of mutation phenotype based on their domain location, and assembly dynamics with WT subunits.Constructs for differentially tagged WT hERG, and LQT2 mutants (G306W, A561V, G601S, F805C, G816V) were co-expressed in HeLa cells.Expression levels and physical association between WT and mutant hERG were assessed with immunoblot and coimmunoprecipitation experiments.Significant decreases in the levels of the mature post-Golgi
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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) | 0.000 | 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) | 0.001 | 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".