Pacemaker channel dysfunction in a patient with sinus node disease

J Clin Invest. 2003 May;111(10):1537-45. doi: 10.1172/JCI16387.


The cardiac pacemaker current I(f) is a major determinant of diastolic depolarization in sinus nodal cells and has a key role in heartbeat generation. Therefore, we hypothesized that some forms of "idiopathic" sinus node dysfunction (SND) are related to inherited dysfunctions of cardiac pacemaker ion channels. In a candidate gene approach, a heterozygous 1-bp deletion (1631delC) in exon 5 of the human HCN4 gene was detected in a patient with idiopathic SND. The mutant HCN4 protein (HCN4-573X) had a truncated C-terminus and lacked the cyclic nucleotide-binding domain. COS-7 cells transiently transfected with HCN4-573X cDNA indicated normal intracellular trafficking and membrane integration of HCN4-573X subunits. Patch-clamp experiments showed that HCN4-573X channels mediated I(f)-like currents that were insensitive to increased cellular cAMP levels. Coexpression experiments showed a dominant-negative effect of HCN4-573X subunits on wild-type subunits. These data indicate that the cardiac I(f) channels are functionally expressed but with altered biophysical properties. Taken together, the clinical, genetic, and in vitro data provide a likely explanation for the patient's sinus bradycardia and the chronotropic incompetence.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Arrhythmia, Sinus / complications
  • Arrhythmia, Sinus / diagnosis*
  • Arrhythmia, Sinus / genetics
  • Atrial Fibrillation / complications
  • Atrial Fibrillation / diagnosis*
  • Atrial Fibrillation / genetics
  • Bradycardia / complications
  • Bradycardia / diagnosis*
  • Bradycardia / genetics
  • COS Cells
  • Cyclic AMP / metabolism
  • Cyclic Nucleotide-Gated Cation Channels
  • DNA Mutational Analysis
  • Electrocardiography
  • Electrophysiologic Techniques, Cardiac
  • Electrophysiology
  • Exons
  • Female
  • Heart Rate / genetics
  • Humans
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Introns
  • Ion Channels / biosynthesis
  • Ion Channels / genetics*
  • Muscle Proteins / biosynthesis
  • Muscle Proteins / genetics*
  • Mutation
  • Patch-Clamp Techniques
  • Potassium Channels
  • Protein Subunits / biosynthesis
  • Protein Subunits / genetics
  • Protein Transport
  • Syncope / etiology
  • Transfection


  • Cyclic Nucleotide-Gated Cation Channels
  • HCN4 protein, human
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels
  • Muscle Proteins
  • Potassium Channels
  • Protein Subunits
  • Cyclic AMP