Intragenic Rescue of the Function of Long QT Syndrome-Causing Mutant hERG K+ Channels
Bibliographic record
Abstract
The human-ether-a-go-go-related gene (hERG) encodes the pore forming subunit of the rapidly activating delayed rectifier K+ channel (IKr), which is important for the repolarization phase of ventricular cardiac action potentials. A reduction in IKr due to a loss of hERG function can lead to long QT syndrome (LQTS). As such, there are a variety of hERG mutations known to cause LQTS. The majority of these mutations are thought to be trafficking deficient, including the G601S mutation. It has been shown that the plasma membrane (PM) expression of the G601S hERG mutant can be rescued by reduced-temperature culture. Additionally, it has been shown that hERG channels undergo rapid internalization in 0 mM K+o culture conditions, but this can also be prevented by reduced-temperature culture. Thus, the hypothesis of this thesis is that certain hERG mutants, including G601S, can traffic to the plasma membrane where they internalize due to impaired stability, similar to WT hERG channels in 0 mM K+ conditions. To test this hypothesis, a secondary mutation, S624T, which does not require K+o for stable PM expression, was added to the G601S mutant hERG channel. The addition of S624T intragenically suppressed the loss-of-function G601S phenotype and significantly rescued G601S expression and current. The addition of S624T also rescued LQTS-causing hERG mutants T474I and P596R. These data reveals the most effective intragenic rescue of LQTS-causing hERG mutants to date and lends insight into the mechanisms underlying the loss-of-function phenotype of certain LQTS-causing hERG mutants.
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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 | 0.000 |
| 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 | 0.001 | 0.001 |
| 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".