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A rare HCN4 variant combined with sick sinus syndrome, left ventricular noncompaction, and complex congenital heart

Fengxiao Zhang1,2, Ning Zhao1,2, Lin Wang3

  • 1Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Channels (Austin, Tex.)
|July 4, 2025
PubMed

Insights

A novel mutation in the hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4) gene was identified. This HCN4 mutation significantly reduces channel function, potentially causing heart conditions like sick sinus syndrome.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Ion Channel Physiology

Background:

  • The hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4) gene is crucial for regulating the heart's spontaneous electrical activity.
  • Mutations in HCN4 are linked to cardiac arrhythmias and conduction disorders, including sick sinus syndrome.

Purpose of the Study:

  • To investigate the functional impact of a novel HCN4 gene mutation (c.2036G>A) associated with cardiac conditions.
  • To determine how the C679Y mutation affects HCN4 channel function and current properties.

Main Methods:

  • Co-expression of wild-type (WT) and mutant (C679Y) HCN4 channels with green fluorescent protein (GFP) in HEK293 cells.
  • Whole-cell patch-clamp electrophysiology to record and analyze HCN4 channel currents.

Main Results:

  • The C679Y HCN4 mutation significantly reduced current amplitude and density compared to WT channels.
  • The C679Y mutation did not substantially alter HCN4 channel current activation kinetics.
  • Analysis of mutant channel deactivation kinetics was limited due to low current.

Conclusions:

  • A novel HCN4 gene mutation (c.2036G>A, C679Y) was identified and functionally characterized.
  • This mutation impairs HCN4 channel function, potentially contributing to bradycardia and other cardiac conditions like left ventricular noncompaction and valve disorders.

Keywords:
HCN4Sick sinus syndromeleft ventricular noncompaction

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