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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, Jahrgang 111, Nr. 10, 01.05.2003, S. 1537-45.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Schulze-Bahr, E, Neu, A, Friederich, P, Kaupp, UB, Breithardt, G, Pongs, O & Isbrandt, D 2003, 'Pacemaker channel dysfunction in a patient with sinus node disease', J CLIN INVEST, Jg. 111, Nr. 10, S. 1537-45. https://doi.org/10.1172/JCI16387

APA

Schulze-Bahr, E., Neu, A., Friederich, P., Kaupp, U. B., Breithardt, G., Pongs, O., & Isbrandt, D. (2003). Pacemaker channel dysfunction in a patient with sinus node disease. J CLIN INVEST, 111(10), 1537-45. https://doi.org/10.1172/JCI16387

Vancouver

Schulze-Bahr E, Neu A, Friederich P, Kaupp UB, Breithardt G, Pongs O et al. Pacemaker channel dysfunction in a patient with sinus node disease. J CLIN INVEST. 2003 Mai 1;111(10):1537-45. https://doi.org/10.1172/JCI16387

Bibtex

@article{c852632b271d42e8aff9336c9d859924,
title = "Pacemaker channel dysfunction in a patient with sinus node disease",
abstract = "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.",
keywords = "Aged, Animals, Arrhythmia, Sinus, Atrial Fibrillation, Bradycardia, COS Cells, Cyclic AMP, Cyclic Nucleotide-Gated Cation Channels, DNA Mutational Analysis, Electrocardiography, Electrophysiologic Techniques, Cardiac, Electrophysiology, Exons, Female, Heart Rate, Humans, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Introns, Ion Channels, Muscle Proteins, Mutation, Patch-Clamp Techniques, Potassium Channels, Protein Subunits, Protein Transport, Syncope, Transfection",
author = "Eric Schulze-Bahr and Axel Neu and Patrick Friederich and Kaupp, {U Benjamin} and G{\"u}nter Breithardt and Olaf Pongs and Dirk Isbrandt",
year = "2003",
month = may,
day = "1",
doi = "10.1172/JCI16387",
language = "English",
volume = "111",
pages = "1537--45",
journal = "J CLIN INVEST",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "10",

}

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 -