A thermoprotective role of the sodium channel β <sub>1</sub> subunit is lost with the β <sub>1</sub> (C121W) mutation
Bibliographic record
Abstract
PURPOSE: A mutation in the β(1) subunit of the voltage-gated sodium (Na(V)) channel, β(1) (C121W), causes genetic epilepsy with febrile seizures plus (GEFS+), a pediatric syndrome in which febrile seizures are the predominant phenotype. Previous studies of molecular mechanisms underlying neuronal hyperexcitability caused by this mutation were conducted at room temperature. The prevalence of seizures during febrile states in patients with GEFS+, however, suggests that the phenotypic consequence of β(1) (C121W) may be exacerbated by elevated temperature. We investigated the putative mechanism underlying seizure generation by the β(1) (C121W) mutation with elevated temperature. METHODS: Whole-cell voltage clamp experiments were performed at 22 and 34°C using Chinese Hamster Ovary (CHO) cells expressing the α subunit of neuronal Na(V) channel isoform, Na(V) 1.2. Voltage-dependent properties were recorded from CHO cells expressing either Na(V) 1.2 alone, Na(V) 1.2 plus wild-type (WT) β(1) subunit, or Na(V) 1.2 plus β(1) (C121W). KEY FINDINGS: Our results suggest WT β(1) is protective against increased channel excitability induced by elevated temperature; protection is lost in the absence of WT β(1) or with expression of β(1) (C121W). At 34°C, Na(V) 1.2 + β(1) (C121W) channel excitability increased compared to NaV1.2 + WT β(1) by the following mechanisms: decreased use-dependent inactivation, increased persistent current and window current, and delayed onset of, and accelerated recovery from, fast inactivation. SIGNIFICANCE: Temperature-dependent changes found in our study are consistent with increased neuronal excitability of GEFS+ patients harboring C121W. These results suggest a novel seizure-causing mechanism for β(1) (C121W): increased channel excitability at elevated temperature.
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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 | 0.000 | 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) | 0.000 | 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".