Novel Germline<i>GJA5</i>/Connexin40 Mutations Associated with Lone Atrial Fibrillation Impair Gap Junctional Intercellular Communication
Bibliographic record
Abstract
Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia worldwide. Here, we investigate the molecular and cellular mechanisms of lone AF-linked germline mutations in the connexin40 (Cx40) gene, GJA5. The entire coding region of GJA5 was sequenced in 68 unrelated patients with lone AF. A novel germline heterozygous missense mutation in Cx40 (p.I75F) was identified in one index patient. The mutation was also present in the proband's father with lone AF but was not found in the unaffected family members who were examined and 200 unrelated healthy control individuals. Electrophysiological studies revealed no electrical coupling of the cell pairs expressing the mutant alone and a significant reduction in gap junction coupling conductance when the mutant was coexpressed with wild-type (wt) Cx40 or Cx43. Interestingly, another lone AF-linked Cx40 mutant p.L229M did not show any apparent coupling defect when expressed alone or together with wt Cx40 but specifically reduced the gap junction coupling when coexpressed with wt Cx43. This study is the first to demonstrate that the germline familial mutations in Cx40 impair the gap junctions through different mechanisms, which may predispose the mutant carriers to AF.
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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 | 0.000 | 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) | 0.001 | 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".