This title appears in the Scientific Report : 2003 

Pacemaker channel dysfunction in a patient with sinus node disease
Schulze-Bahr, E.
Neu, A. / Friederich, P. / Kaupp, U. B. / Breithardt, G. / Pongs, O. / Isbrandt, D.
Zelluläre Signalverarbeitung; IBI-1
The @journal of clinical investigation, 111 (2003) S. 1537 - 1545
Ann Arbor, Mich. ASCJ 2003
1537 - 1545
10.1172/JCI200316387
Journal Article
Neurowissenschaften
Journal of Clinical Investigation 111
J
Please use the identifier: http://dx.doi.org/10.1172/JCI200316387 in citations.
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 It-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.