Key result
Heterozygous HCN4 deletion causes dominant-negative, cAMP-insensitive pacemaker channels in sinus node dysfunction.
Why the study?
Does the HCN4-1631delC mutation alter the biophysical properties of cardiac pacemaker channels in a patient with idiopathic sinus node dysfunction?
Does the HCN4-1631delC mutation alter the biophysical properties of cardiac pacemaker channels in a patient with idiopathic sinus node dysfunction?
This study identifies a genetic defect in the HCN4 pacemaker channel that explains chronotropic incompetence and sinus bradycardia in familial idiopathic sinus node dysfunction.
May explain select idiopathic sinus node dysfunction cases; leaves open HCN4 screening or targeted therapies.
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.
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Schulze‐Bahr et al. (2003) studied Idiopathic sinus node dysfunction (n=10). HCN4 gene mutation (1631delC) vs. Wild-type HCN4 channels was evaluated on Electrophysiological properties and cAMP sensitivity of mutant HCN4 channels in vitro. A heterozygous 1-bp deletion in the HCN4 gene was identified in a patient with idiopathic sinus node dysfunction, yielding dominant-negative mutant pacemaker channels that are insensitive to cAMP.
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