Identification of two novel mutations in the <i>CACNA1A</i> gene responsible for episodic ataxia type 2
Bibliographic record
Abstract
Editor—Episodic ataxia type 2 (EA-2) (OMIM 108500) is an autosomal dominant neurological disorder. Affected subjects experience discrete episodes of cerebellar ataxia usually associated with migraine symptoms, interictal nystagmus, as well as residual mild and, in some cases, a progressive cerebellar incoordination. These attacks usually begin in childhood or adolescence, last a few hours, may be precipitated by stress, exercise, or fatigue, and respond to acetazolamide.1-3 As with other acetazolamide responsive diseases, EA-2 is a channelopathy.4 It was first linked to chromosome 19p133 5-7 and subsequently shown to be allelic to familial hemiplegic migraine (FHM) when mutations for both disorders were identified in the P/Q type calcium channel α1Asubunit gene, CACNA1A .8 Shortly thereafter, an intragenic expansion of a CAG repeat within CACNA1A was shown to cause spinocerebellar ataxia type 6 (SCA6).9 To date, mutations causing EA-2 all appear to disrupt the translational reading frame of the α1A subunit gene,8 10-12 while those causing FHM all seem to be missense mutations.8 13-15 A single missense mutation, however, in the CACNA1A gene has also been shown to cause severe progressive cerebellar ataxia.16 The α1A subunit has been shown to be the pore forming unit of the P/Q type calcium channel17 18 which is involved in controlling neurotransmitter release19 and is expressed throughout the brain with abundant expression in the cerebellum.20-22 This high voltage activated calcium channel consists of five subunits, α1A, β4, α2, δ, and γ. The α1A subunit is subdivided into four homologous domains (DI-DIV) that each contain six putative transmembrane regions (S1-S6) (fig 1).19 The fourth transmembrane domain functions as the voltage sensor while the four loops between transmembrane domains S5-S6 compose the pore …
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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 | 0.001 | 0.006 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.002 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".