title: Altered HCN4 channel C-linker interaction is associated with familial tachycardia-bradycardia syndrome and atrial fibrillation.
abstract: OBJECTIVE
  HCN4 channels are involved in generation, regulation, and stabilization of heart rhythm and channel dysfunction is associated with inherited sinus bradycardia. We asked whether dysfunctional HCN4 channels also contribute to the generation of cardiac tachyarrhythmias.
  
  
  RESULTS
  In a candidate gene approach, we screened 422 patients with atrial and/or ventricular tachyarrhythmias and detected a novel HCN4 gene mutation that replaced the positively charged lysine 530 with an asparagine (HCN4-K530N) in a highly conserved region of the C-linker. The index patient developed tachycardia-bradycardia syndrome and persistent atrial fibrillation (AF) in an age-dependent fashion. Pedigree analysis identified eight affected family members with a similar course of disease. Whole-cell patch clamp electrophysiology of HEK293 cells showed that homomeric mutant channels almost are indistinguishable from wild-type channels. In contrast, heteromeric channels composed of mutant and wild-type subunits displayed a significant hyperpolarizing shift in the half-maximal activation voltage. This may be caused by a shift in the equilibrium between the tonically inhibited nucleotide-free state of the C-terminal domain of HCN4 believed to consist of a 'dimer of dimers' and the activated ligand-bound tetrameric form, leading to an increased inhibition of activity in heteromeric channels.
  
  
  CONCLUSIONS
  Altered C-linker oligomerization in heteromeric channels is considered to promote familial tachycardia-bradycardia syndrome and persistent AF, indicating that f-channel dysfunction contributes to the development of atrial tachyarrhythmias.
authors.affiliation: Institute for Physiology and Pathophysiology, University of Heidelberg, INF 326, Heidelberg D-69120, Germany.
authors.forename: Nana
authors.initials: N
authors.lastname: Duhme
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Schweizer
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Becker
authors.forename: Julian
authors.initials: J
authors.lastname: Schröter
authors.forename: Thomas R M
authors.initials: TR
authors.lastname: Barends
authors.forename: Ilme
authors.initials: I
authors.lastname: Schlichting
authors.forename: Andreas
authors.initials: A
authors.lastname: Draguhn
authors.forename: Claus
authors.initials: C
authors.lastname: Bruehl
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Michael
authors.initials: M
authors.lastname: Koenen
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001281:Atrial Fibrillation / Q000235:genetics*; D001919:Bradycardia / Q000235:genetics*; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000737:chemistry / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D013610:Tachycardia / Q000235:genetics*
chemical_list: D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels