Pacemaker channel dysfunction in a patient with sinus node disease.
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.
Schulze-Bahr
Eric
E
Genetics of Arrhythmias, Molecular Cardiology Section, Institute for Arteriosclerosis Research, University of Münster, Münster, Germany. heart@uni-muenster.de
Neu
Axel
A
Friederich
Patrick
P
Kaupp
U Benjamin
UB
Breithardt
Günter
G
Pongs
Olaf
O
Isbrandt
Dirk
D
D000368:Aged; D000818:Animals; D001146:Arrhythmia, Sinus / Q000150:complications / Q000175:diagnosis* / Q000235:genetics; D001281:Atrial Fibrillation / Q000150:complications / Q000175:diagnosis* / Q000235:genetics; D001919:Bradycardia / Q000150:complications / Q000175:diagnosis* / Q000235:genetics; D019556:COS Cells; D000242:Cyclic AMP / Q000378:metabolism; D054815:Cyclic Nucleotide-Gated Cation Channels; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D004594:Electrophysiology; D005091:Exons; D005260:Female; D006339:Heart Rate / Q000235:genetics; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007438:Introns; D007473:Ion Channels / Q000096:biosynthesis / Q000235:genetics*; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics*; D009154:Mutation; D018408:Patch-Clamp Techniques; D015221:Potassium Channels; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics; D021381:Protein Transport; D013575:Syncope / Q000209:etiology; D014162:Transfection
D054815:Cyclic Nucleotide-Gated Cation Channels; C119587:HCN4 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D009124:Muscle Proteins; D015221:Potassium Channels; D021122:Protein Subunits; D000242:Cyclic AMP