Pacemaker channel dysfunction in a patient with sinus node disease
Eric Schulze-Bahr, … , Olaf Pongs, Dirk Isbrandt
Eric Schulze-Bahr, … , Olaf Pongs, Dirk Isbrandt
Published May 15, 2003
Citation Information: J Clin Invest. 2003;111(10):1537-1545. https://doi.org/10.1172/JCI16387.
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Article Cardiology

Pacemaker channel dysfunction in a patient with sinus node disease

Abstract

The cardiac pacemaker current If 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 If-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 If 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.

Authors

Eric Schulze-Bahr, Axel Neu, Patrick Friederich, U. Benjamin Kaupp, Günter Breithardt, Olaf Pongs, Dirk Isbrandt

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Mutation detection in the HCN4 gene. (a) The human HCN4 gene consists of...
Mutation detection in the HCN4 gene. (a) The human HCN4 gene consists of eight exons. The minimal exon size was 141 bp (exon 5), and the maximal size was 1,465 bp (exon 8); the largest intron was intron 1 (∼24 kb) and the smallest intron 5 (102 bp). The functional domains of the wild-type HCN4 channel are delineated below. P, pore region; 1–6, transmembrane domains. (b) Electropherogram after direct sequencing of an index patient with SND. A heterozygous 1-bp deletion (1631delC) in HCN4 resulted in a superimposing sequence pattern consisting of the wild-type and mutant exon 5 sequence. (c) The heterozygous deletion mutation induces an EciI restriction site in exon 5; after restriction enzyme analysis, the uncut wild-type fragment (380 bp) and two EciI fragments (200 and 180 bp, cut mutant fragment) were found in the index patient. Her three healthy children had the wild-type configuration. The left lane shows the size standard in base pairs (pUC19 DNA/MspI). (d) Schematic topology of HCN4 channels with six transmembrane segments (S1–S6) and intracellular N- and C-termini. Because of the reading frame shift in the nucleotide sequence, a resulting premature stop codon deleted the C-terminally located cNBD in HCN4-573X that is replaced by 29 novel amino acids (thick gray line). The relative sizes of the transmembrane segments and N- or C-termini are not drawn to scale.