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Mutation in S6 domain of HCN4 channel in patient with suspected Brugada syndrome modifies channel function

  • Ion channels, receptors and transporters
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Abstract

Diseases such as the sick sinus and the Brugada syndrome are cardiac abnormalities, which can be caused by a number of genetic aberrances. Among them are mutations in HCN4, a gene, which encodes the hyperpolarization-activated, cyclic nucleotide-gated ion channel 4; this pacemaker channel is responsible for the spontaneous activity of the sinoatrial node. The present genetic screening of patients with suspected or diagnosed Brugada or sick sinus syndrome identified in 1 out of 62 samples the novel mutation V492F. It is located in a highly conserved site of hyperpolarization-activated cyclic nucleotide-gated (HCN)4 channel downstream of the filter at the start of the last transmembrane domain S6. Functional expression of mutant channels in HEK293 cells uncovered a profoundly reduced channel function but no appreciable impact on channel synthesis and trafficking compared to the wild type. The inward rectifying HCN4 current could be partially rescued by an expression of heteromeric channels comprising wt and mutant monomers. These heteromeric channels were responsive to cAMP but they required a more negative voltage for activation and they exhibited a lower current density than the wt channel. This suggests a dominant negative effect of the mutation in patients, which carry this heterozygous mutation. Such a modulation of HCN4 activity could be the cause of the diagnosed cardiac abnormality.

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Acknowledgments

This work was supported by grant no. PGR00139 from MAECI (Ministero affari esteri e cooperazione internazionale), CARIPLO grants 2014-0660 to AM and grant 2014-0728 to DD.

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Authors and Affiliations

  1. Institute of Legal Medicine, University of Frankfurt, Kennedyallee 104, 60596, Frankfurt am Main, Germany

    Stephanie Biel & Silke Kauferstein

  2. Department of Biosciences and CNR IBF-Mi, University of Milano, Via Celoria 26, 20133, Milan, Italy

    Marco Aquila & Anna Moroni

  3. Department of Biology, Plant Membrane Biophysics, Technische Universität Darmstadt, Schnittspahnstrasse 3, 64287, Darmstadt, Germany

    Brigitte Hertel, Anne Berthold & Gerhard Thiel

  4. Kerckhoff Heart and Thorax Center, University of Giessen, Benekestraße 2, 61231, Bad Nauheim, Germany

    Thomas Neumann

  5. The PaceLab, Department of Biosciences, University of Milano, via Celoria 26, 20133, Milan, Italy

    Dario DiFrancesco

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  1. Stephanie Biel
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  2. Marco Aquila
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  3. Brigitte Hertel
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Correspondence to Gerhard Thiel.

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Stephanie Biel and Marco Aquila contributed equally to this work.

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Biel, S., Aquila, M., Hertel, B. et al. Mutation in S6 domain of HCN4 channel in patient with suspected Brugada syndrome modifies channel function. Pflugers Arch - Eur J Physiol 468, 1663–1671 (2016). https://doi.org/10.1007/s00424-016-1870-1

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  • DOI: https://doi.org/10.1007/s00424-016-1870-1

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