[HTML][HTML] Pacemaker channel dysfunction in a patient with sinus node disease

E Schulze-Bahr, A Neu, P Friederich… - The Journal of …, 2003 - Am Soc Clin Investig
E Schulze-Bahr, A Neu, P Friederich, UB Kaupp, G Breithardt, O Pongs, D Isbrandt
The Journal of clinical investigation, 2003Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation