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  The C-terminal HCN4 variant P883R alters channel properties and acts as genetic modifier of atrial fibrillation and structural heart disease

Weigl, I., Geschwill, P., Reiss, M., Bruehl, C., Draguhn, A., Koenen, M., et al. (2019). The C-terminal HCN4 variant P883R alters channel properties and acts as genetic modifier of atrial fibrillation and structural heart disease. Biochemical and Biophysical Research Communications, 519(1), 141-147. doi:10.1016/j.bbrc.2019.08.150.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0004-9E25-1 Version Permalink: http://hdl.handle.net/21.11116/0000-0005-63CB-7
Genre: Journal Article

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 Creators:
Weigl, Isabel, Author
Geschwill, Pascal, Author
Reiss, Miriam, Author
Bruehl, Claus, Author
Draguhn, Andreas, Author
Koenen, Michael1, 2, 3, Author              
Sedaghat-Hamedani, Farbod, Author
Meder, Benjamin, Author
Thomas, Dierk, Author
Katus, Hugo A., Author
Schweizer, Patrick A., Author
Affiliations:
1Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497704              
2Department of Cell Physiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497701              
3Molecular anatomy of the neuromuscular junction, Max Planck Institute for Medical Research, Max Planck Society, ou_1497727              

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Free keywords: Atrial fibrillation; Genetic modifier; HCN4; Tachycardia-induced cardiomyopathy
 Abstract: Atrial fibrillation (AF) is the most frequent sustained arrhythmia and can lead to structural cardiac changes, known as tachycardia-induced cardiomyopathy (TIC). HCN4 is implicated in spontaneous excitation of the sinoatrial node, while channel dysfunction has been associated with sinus bradycardia, AF and structural heart disease. We here asked whether HCN4 mutations may contribute to the development of TIC, as well. Mutation scanning of HCN4 in 60 independent patients with AF and suspected TIC followed by panel sequencing in carriers of HCN4 variants identified the HCN4 variant P883R [minor allele frequency (MAF): 0,88%], together with the KCNE1 variant S38G (MAF: 65%) in three unrelated patients. Family histories revealed additional cases of AF, sudden cardiac death and cardiomyopathy. Patch-clamp recordings of HCN4-P883R channels expressed in HEK293 cells showed remarkable alterations of channel properties shifting the half-maximal activation voltage to more depolarized potentials, while channel deactivation was faster compared to wild-type (WT). Co-transfection of WT and mutant subunits, resembling the heterozygous cellular situation of our patients, revealed significantly higher current densities compared to WT. In conclusion HCN4-P883R may increase ectopic trigger and maintenance of AF by shifting the activation voltage of If to more positive potentials and producing higher current density. Together with the common KCNE1 variant S38G, previously proposed as a genetic modifier of AF, HCN4-P883R may provide a substrate for the development of AF and TIC.

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Language(s): eng - English
 Dates: 2019-08-152019-08-262019-08-312019-10-29
 Publication Status: Published in print
 Pages: 7
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 Table of Contents: -
 Rev. Method: Peer
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Title: Biochemical and Biophysical Research Communications
  Other : Biochem. Biophys. Res. Commun.
Source Genre: Journal
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Publ. Info: Orlando, Fla. : Academic Press
Pages: - Volume / Issue: 519 (1) Sequence Number: - Start / End Page: 141 - 147 Identifier: ISSN: 0006-291X
CoNE: https://pure.mpg.de/cone/journals/resource/954922652205_1