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Non dominant-negative KCNJ2 gene mutations leading to Andersen-Tawil syndrome with an isolated cardiac phenotype

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Abstract

Andersen-Tawil syndrome (ATS) is characterized by dysmorphic features, periodic paralyses and abnormal ventricular repolarization. After genoty** a large set of patients with congenital long-QT syndrome, we identified two novel, heterozygous KCNJ2 mutations (p.N318S, p.W322C) located in the C-terminus of the Kir2.1 subunit. These mutations have a different localization than classical ATS mutations which are mostly located at a potential interaction face with the slide helix or at the interface between the C-termini. Mutation carriers were without the key features of ATS, causing an isolated cardiac phenotype. While the N318S mutants regularly reached the plasma membrane, W322C mutants primarily resided in late endosomes. Co-expression of N318S or W322C with wild-type Kir2.1 reduced current amplitudes only by 20–25 %. This mild loss-of-function for the heteromeric channels resulted from defective channel trafficking (W322C) or gating (N318S). Strikingly, and in contrast to the majority of ATS mutations, neither mutant caused a dominant-negative suppression of wild-type Kir2.1, Kir2.2 and Kir2.3 currents. Thus, a mild reduction of native Kir2.x currents by non dominant-negative mutants may cause ATS with an isolated cardiac phenotype.

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Abbreviations

CPVT:

Catecholaminergic polymorphic ventricular tachycardia

EGFP:

Enhanced green fluorescent protein

PIP2 :

Phosphatidylinositol-4,5-bisphosphate

PMVT:

Polymorphic ventricular tachycardia

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Acknowledgments

We would like to thank Kirsten Ramlow and Oxana Nowak for excellent technical support, Ruth Bennett, the ExoSeq team, the staff of the WTSI for their invaluable contribution to the manuscript. This work was supported by Deutsche Forschungs-gemeinschaft (DFG) Grant DE1482-3/2 to N.D., The Fondation Leducq, Paris (to E. S.-B.), and by the Wellcome Trust (Grant number 098051).

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Institut für Physiologie und Pathophysiologie, Vegetative Physiologie, Philipps-University Marburg, Deutschhausstraße 1-2, 35037, Marburg, Germany

    Maren M. Limberg, Michael F. Netter, Susanne Rinné & Niels Decher

  2. Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Münster, Germany

    Sven Zumhagen, Doris Böckelmann, Birgit Stallmeyer & Eric Schulze-Bahr

  3. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK

    Alison J. Coffey & Jane Rogers

  4. Department of Biochemistry, University of Cambridge, Hopkins Building, Tennis Court Road, Cambridge, CB2 1QW, UK

    Andrew Grace

  5. Papworth Hospital, Cambridge, CB23 3RE, UK

    Andrew Grace

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  1. Maren M. Limberg
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Correspondence to Niels Decher.

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M. M. Limberg and S. Zumhagen contributed equally.

Niels Decher and Eric Schulze-Bahr are co-senior authors.

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Limberg, M.M., Zumhagen, S., Netter, M.F. et al. Non dominant-negative KCNJ2 gene mutations leading to Andersen-Tawil syndrome with an isolated cardiac phenotype. Basic Res Cardiol 108, 353 (2013). https://doi.org/10.1007/s00395-013-0353-1

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