May 15, 2003Open Access
Pacemaker channel dysfunction in a patient with sinus node disease
Key Result
A heterozygous deletion in the HCN4 gene (HCN4-573X) in a patient with idiopathic sinus node dysfunction resulted in mutant channels that were insensitive to cAMP and exerted a dominant-negative effect.
Study Design
Type
Case Report (n=1)
Structured PICO
Does a mutation in the HCN4 pacemaker channel cause idiopathic sinus node dysfunction?
P
Population
1 patient with idiopathic sinus node dysfunction who underwent genetic screening and subsequent in vitro functional analysis of a detected HCN4 mutation.
E
Exposure
Genetic screening of HCN4 gene and in vitro functional characterization of mutant HCN4-573X channels
C
Comparator
Wild-type HCN4 subunits (in vitro)
O
Outcome
Identification of genetic mutation and functional properties of the mutant pacemaker channel (I(f))surrogate
This study provides genetic and functional evidence that a mutation in the HCN4 gene can cause idiopathic sinus node dysfunction and chronotropic incompetence.
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.