HCN4 Mutation Causing Familial Inappropriate Sinus Tachycardia Leads to a Conformational Change Mimicking cAMP Binding and Induces Constitutive Channel Activity
Bibliographic record
Abstract
BACKGROUND: Inappropriate sinus tachycardia (IST) is an arrhythmia characterized by rapid sinus rates of over 100 bpm at rest. The mechanisms underlying this often-debilitating condition are not fully understood. The differential diagnosis for this persistent observation is broad, including medication side effects or serendipitous use of chronotropic stimulating drugs. Genetic causes of IST are seldom considered. Only 2 mutations have been linked to this condition, both of which affect the gene encoding HCN4 channels, which play an important role in generating pacemaker activity of the sinoatrial node. METHODS: Standard clinical genetic testing was performed on a child with IST, her affected mother, and 2 healthy siblings. A novel HCN4 channel variant identified in the family was studied by whole-cell patch clamp analysis. Three-dimensional protein structures of mutant and wild-type HCN4 channels were generated and subjected to 200 ns of unrestricted molecular dynamics simulation. RESULTS: A heterozygous, missense variant was identified in the HCN4 gene (p.N299S) in the affected child and mother, while absent in 2 healthy siblings of the child. Patch clamp analysis revealed significantly increased HCN4 current density and a rightward-shifted activation curve in cells expressing p.N299S- HCN4 versus wild-type channels, suggesting constitutive activity of the mutant HCN4 channel. In molecular dynamics simulations, the voltage sensor of p.N299S- HCN4 channels adopted a resting conformation mimicking that of cAMP-bound wild-type HCN4 , providing a structural basis for the functional observations. Ivabradine application returned the gain-of-function properties of mutant channels to baseline levels. CONCLUSIONS: We identified a gain-of-function HCN4 variant in a family with IST that displays constitutive activity and structurally mimics the effects of cAMP activation. This study furthers our understanding of the mechanisms underlying IST and provides data supporting the efficacious effect of ivabradine in genetically based IST.
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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) | 0.001 | 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".