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  Altered HCN4 channel C-linker interaction is associated with familial tachycardia–bradycardia syndrome and atrial fibrillation

Duhme, N., Schweizer, P., Thomas, D., Becker, R., Schröter, J., Barends, T., et al. (2013). Altered HCN4 channel C-linker interaction is associated with familial tachycardia–bradycardia syndrome and atrial fibrillation. European Heart Journal, 34(35), 2768-2775. doi:10.1093/eurheartj/ehs391.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0019-9030-3 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0019-9031-1
Genre: Journal Article

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EurHeartJ_34_2013_2768.pdf (Any fulltext), 723KB
 
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 Creators:
Duhme, Nana, Author
Schweizer, Patrick1, Author              
Thomas, Dierk, Author
Becker, Rüdiger, Author
Schröter, Julian, Author
Barends, Thomas2, Author              
Schlichting, Ilme2, Author              
Draguhn, Andreas, Author
Bruehl, Claus, Author
Katus, Hugo A., Author
Koenen, Michael1, Author              
Affiliations:
1Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497704              
2Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society, ou_1497700              

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Free keywords: Sinoatrial node † HCN4 † Atrial fibrillation † Tachyarrhythmia † Ion channels † Pacemake
 Abstract: 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. Methods and 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 persist- ent 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. Conclusion 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 tachyarrhythmia

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Language(s): eng - English
 Dates: 2012-06-042012-10-252012-11-232013-09-01
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.1093/eurheartj/ehs391
Other: 7832
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Title: European Heart Journal
  Other : Eur. Heart J.
Source Genre: Journal
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Pages: - Volume / Issue: 34 (35) Sequence Number: - Start / End Page: 2768 - 2775 Identifier: ISSN: 0195-668X
CoNE: https://pure.mpg.de/cone/journals/resource/954925625319