Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel.
We found that sinus bradycardia in members of a large family was associated with a mutation in the gene coding for the pacemaker HCN4 ion channel. Pacemaker channels of the sinoatrial node generate spontaneous activity and mediate cyclic AMP (cAMP)-dependent autonomic modulation of the heart rate. The mutation associated with bradycardia is located near the cAMP-binding site; functional analysis found that mutant channels respond normally to cAMP but are activated at more negative voltages than are wild-type channels. These changes, which mimic those of mild vagal stimulation, slow the heart rate by decreasing the inward diastolic current. Thus, diminished function of pacemaker channels is linked to familial bradycardia.
Milanesi
Raffaella
R
Department of Biomolecular Sciences and Biotechnology, Laboratory of Molecular Physiology and Neurobiology, University of Milan, Milan, Italy.
Baruscotti
Mirko
M
Gnecchi-Ruscone
Tomaso
T
DiFrancesco
Dario
D
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D001146:Arrhythmia, Sinus / Q000235:genetics; D001483:Base Sequence; D001919:Bradycardia / Q000235:genetics*; D002648:Child; D054815:Cyclic Nucleotide-Gated Cation Channels; D004594:Electrophysiology; D005260:Female; D008040:Genetic Linkage; D006329:Heart Conduction System; D006339:Heart Rate; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D015221:Potassium Channels; D012689:Sequence Homology, Nucleic Acid
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