A mutant HCN4 channel in a family with bradycardia, left bundle branch block, and left ventricular noncompaction

Heart Vessels. 2018 Jul;33(7):802-819. doi: 10.1007/s00380-018-1116-6. Epub 2018 Jan 18.


We found that a female infant presenting with left bundle branch block and left ventricular noncompaction carries uninvestigated gene mutations HCN4(G811E), SCN5A(L1988R), DMD(S2384Y), and EMD(R203H). Here, we explored the possible pathogenicity of HCN4(G811E), which results in a G811E substitution in hyperpolarization-activated cyclic nucleotide-gated channel 4, the main subunit of the cardiac pacemaker channel. Voltage-clamp measurements in a heterologous expression system of HEK293T cells showed that HCN4(G811E) slightly reduced whole-cell HCN4 channel conductance, whereas it did not affect the gating kinetics, unitary conductance, or cAMP-dependent modulation of voltage-dependence. Immunocytochemistry and immunoblot analysis showed that the G811E mutation did not impair the membrane trafficking of the channel subunit in the heterologous expression system. These findings indicate that HCN4(G811E) may not be a monogenic factor to cause the cardiac disorders.

Keywords: Arrhythmia; Cardiac channelopathy; Cardiomyopathy; I f; Pacemaker current.

MeSH terms

  • Bradycardia / diagnosis
  • Bradycardia / etiology
  • Bradycardia / genetics*
  • Bundle-Branch Block / complications
  • Bundle-Branch Block / diagnosis
  • Bundle-Branch Block / genetics*
  • DNA Mutational Analysis
  • Echocardiography, Doppler, Color
  • Female
  • HEK293 Cells
  • Heart Defects, Congenital / complications
  • Heart Defects, Congenital / diagnosis
  • Heart Defects, Congenital / genetics*
  • Heart Ventricles / abnormalities*
  • Humans
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / genetics*
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / metabolism
  • Immunoblotting
  • Immunohistochemistry
  • Infant, Newborn
  • Muscle Proteins / genetics*
  • Muscle Proteins / metabolism
  • Mutation*
  • Potassium Channels / genetics*
  • Potassium Channels / metabolism
  • Sinoatrial Node / metabolism
  • Sinoatrial Node / pathology


  • HCN4 protein, human
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Muscle Proteins
  • Potassium Channels