Both gain‐of‐function and loss‐of‐function <i> de novo <scp>CACNA</scp> 1A </i> mutations cause severe developmental epileptic encephalopathies in the spectrum of Lennox‐Gastaut syndrome
Bibliographic record
Abstract
Abstract Objective Developmental epileptic encephalopathies ( DEE s) are genetically heterogeneous severe childhood‐onset epilepsies with developmental delay or cognitive deficits. In this study, we explored the pathogenic mechanisms of DEE ‐associated de novo mutations in the CACNA 1A gene. Methods We studied the functional impact of four de novo DEE ‐associated CACNA 1A mutations, including the previously described p.A713T variant and three novel variants (p.V1396M, p.G230V, and p.I1357S). Mutant cDNA s were expressed in HEK 293 cells, and whole‐cell voltage‐clamp recordings were conducted to test the impacts on Ca V 2.1 channel function. Channel localization and structure were assessed with immunofluorescence microscopy and three‐dimensional (3D) modeling. Results We find that the G230V and I1357S mutations result in loss‐of‐function effects with reduced whole‐cell current densities and decreased channel expression at the cell membrane. By contrast, the A713T and V1396M variants resulted in gain‐of‐function effects with increased whole‐cell currents and facilitated current activation (hyperpolarized shift). The A713T variant also resulted in slower current decay. 3D modeling predicts conformational changes favoring channel opening for A713T and V1396M. Significance Our findings suggest that both gain‐of‐function and loss‐of‐function CACNA 1A mutations are associated with similarly severe DEE s and that functional validation is required to clarify the underlying molecular mechanisms and to guide therapies.
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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".