Mutation of an L-Type Calcium Channel Gene Leads to a Novel Human Primary Cellular Immunodeficiency
Bibliographic record
Abstract
Abstract Human primary immunodeficiencies are inherited diseases that can provide valuable insight into the immune system. Calcium (Ca 2+ ) is a vital secondary messenger in T lymphocytes regulating a vast array of important events including maturation, homeostasis, activation, and apoptosis and can enter the cell through CRAC, TRP, and Cav channels. Here we describe three Cav1.4-deficient siblings presenting with X-linked incomplete congenital stationary night blindness as well as an immune phenotype characterized by several recurrent infections. Complete exome sequencing demonstrated that the patients share only a single pathogenic allele; a R625X (p.Arg625Ter) point mutation that leads to a premature stop codon in the CACNA1F gene encoding the L-type Ca 2+ channel Cav1.4. The subjects uniformly exhibited an expansion of central and effector memory T lymphocytes, and evidence of T lymphocytes exhaustion with corresponding upregulation of inhibitory receptors. Moreover, the sustained elevated levels of activation markers on B lymphocytes suggest that they are in a chronic state of activation. Finally, the T lymphocytes from patients and CACNA1F knockdown Jurkat T lymphocytes exhibited a reduced Ca 2+ flux, compared to controls. This is the first example where the mutation of any Cav channel causes a primary immunodeficiency in humans and establishes the physiological importance of Cav channels in the human immune system.
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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 | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".