Abstract 639: Destabilization Of The Open State Of <i>I</i> <sub> <i>Ks</i> </sub> Potassium Channels By A KCNQ1 V205M Missense Mutation Causes An Inherited Form Of LQTS In A Canadian Aboriginal Community
Bibliographic record
Abstract
Hereditary long QT syndrome (LQTS) is a genetic disease characterized by a prolonged QT interval in the electrocardiogram and an increased likelihood of serious ventricular arrhythmias. We have determined that LQTS is disproportionately prevalent in a Northern British Columbia aboriginal community. Genetic screening of affected individuals revealed a novel missense mutation (V205M) in the S3 transmembrane helix of KCNQ1, the pore forming domain of the I K s channel complex. Co-expression of V205M KCNQ1 in mammalian cells with the accessory subunit KCNE1 recapitulated I Ks , with similar surface expression to wild type (Wt) channels, but with a 33.7 mV depolarizing shift in the V 1/2 of activation. This was accompanied by a slowing of channel activation (294 ± 85 ms, n=5; and 878 ± 124 ms, n=4; for Wt and V205M channels, respectively, at +70 mV), and an acceleration of deactivation (53 ± 3.6 ms, n=5; and 14 ± 3.5, n=4; for Wt and V205M channels, at −100 mV), determined at 35°C. The heterozygous state of the channel complex was simulated by co-expressing Wt and V205M channel subunits, and this resulted in phenotypic I Ks currents with properties intermediate between Wt and V205M homomultimeric channels. Using a ventricular action potential voltage clamp protocol applied at 3 Hz, Wt channels, but not V205M channels, accumulated in the open state, which resulted in large outward I Ks currents only for Wt channels. The outward ionic charge through heteromultimeric channels during the action potential clamp was reduced by more than 75% compared to Wt channels, suggesting a functional dominant negative effect of the V205M mutation at high heart rates. The changes in I Ks kinetics produced by the V205M mutation are expected to decrease current and reduce the repolarization reserve during the cardiac ventricular action potential, with a likely increased susceptibility to the initiation of arrhythmias, especially during periods of high sympathetic drive.
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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 | 0.001 | 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) | 0.002 | 0.001 |
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".