Arrhythmias & electrophysiology
HCN4 Mutation Causing Familial Inappropriate Sinus Tachycardia Leads to a Conformational Change Mimicking cAMP Binding and Induces Constitutive Channel Activity
Authors' conclusion
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.
Study context
- Population
- A child with inappropriate sinus tachycardia (IST), her affected mother, and 2 healthy siblings
- Comparison
- Cells expressing p.N299S- HCN4 versus wild-type channels
- Outcome
- HCN4 genetic variant
Methodological detailswhole-cell patch clamp analysis, 200 ns of unrestricted molecular dynamics simulation
- Whole-cell patch clamp analysis
- 200 ns of unrestricted molecular dynamics simulation
Main finding
As reported in the abstract
- Heterozygous missense HCN4 variant (p.N299S) in affected child and mother, absent in 2 healthy siblings
Further findings
HCN4 current density and activation curve
- Significantly increased HCN4 current density and rightward-shifted activation curve with p.N299S- HCN4 versus wild-type, suggesting constitutive activity
Voltage sensor conformation (molecular dynamics)
- Voltage sensor of p.N299S- HCN4 adopted a resting conformation mimicking cAMP-bound wild-type HCN4
Effect of ivabradine on mutant channels
- Ivabradine returned gain-of-function properties of mutant channels to baseline levels
Original publication
HCN4 Mutation Causing Familial Inappropriate Sinus Tachycardia Leads to a Conformational Change Mimicking cAMP Binding and Induces Constitutive Channel Activity. Circ Arrhythm Electrophysiol. Published 14 October 2025. doi:10.
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