Pacemaker channel dysfunction in a patient with sinus node disease
Standard
Pacemaker channel dysfunction in a patient with sinus node disease. / Schulze-Bahr, Eric; Neu, Axel; Friederich, Patrick; Kaupp, U Benjamin; Breithardt, Günter; Pongs, Olaf; Isbrandt, Dirk.
In: J CLIN INVEST, Vol. 111, No. 10, 01.05.2003, p. 1537-45.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Pacemaker channel dysfunction in a patient with sinus node disease
AU - Schulze-Bahr, Eric
AU - Neu, Axel
AU - Friederich, Patrick
AU - Kaupp, U Benjamin
AU - Breithardt, Günter
AU - Pongs, Olaf
AU - Isbrandt, Dirk
PY - 2003/5/1
Y1 - 2003/5/1
N2 - 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.
AB - 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.
KW - Aged
KW - Animals
KW - Arrhythmia, Sinus
KW - Atrial Fibrillation
KW - Bradycardia
KW - COS Cells
KW - Cyclic AMP
KW - Cyclic Nucleotide-Gated Cation Channels
KW - DNA Mutational Analysis
KW - Electrocardiography
KW - Electrophysiologic Techniques, Cardiac
KW - Electrophysiology
KW - Exons
KW - Female
KW - Heart Rate
KW - Humans
KW - Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
KW - Introns
KW - Ion Channels
KW - Muscle Proteins
KW - Mutation
KW - Patch-Clamp Techniques
KW - Potassium Channels
KW - Protein Subunits
KW - Protein Transport
KW - Syncope
KW - Transfection
U2 - 10.1172/JCI16387
DO - 10.1172/JCI16387
M3 - SCORING: Journal article
C2 - 12750403
VL - 111
SP - 1537
EP - 1545
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 10
ER -