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Lamin-A/C variants found in patients with cardiac conduction disease reduce sodium currents

Michael A. Olaopa, Katherine G. Spoonamore, Deepak Bhakta, Zhenhui Chen, Patricia B.S. Celestino-Soper, Peng-Sheng Chen, Tomohiko Ai, Matteo Vatta
  • Michael A. Olaopa
    Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
  • Katherine G. Spoonamore
    Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
  • Deepak Bhakta
    Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
  • Zhenhui Chen
    Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
  • Patricia B.S. Celestino-Soper
    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
  • Peng-Sheng Chen
    Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
  • Tomohiko Ai
    Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; Division of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan | ait@iu.edu
  • Matteo Vatta
    Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States

Abstract

Variants in the LMNA gene, which encodes Lamin-A/C, have been commonly associated with cardiac conduction system diseases usually accompanying cardiomyopathy. We have seen two unrelated patients who presented with atrioventricular block (AVB) with or without cardiomyopathy. Genetic testing identified the LMNA missense variant c.1634G>A (p.R545H) and the single nucleotide deletion c.859delG (p.A287Lfs*193). The deletion leads to a shift in the reading frame and subsequent protein truncation. Since impaired Nav1.5 function has been reported to cause AVB, we sought to investigate the effects of abnormal Lamins on Nav1.5 in HEK-293 cells using patch-clamp methods. Patch-clamp studies showed that p.R545H decreased the peak INa by approximately 70%. The voltage-dependency of steady state inactivation was rightward shifted in the cells transfected with p.R545H. The p.A287Lfs*193 also decreased the peak INa by approximately 62%. The voltagedependency of steady state inactivation was rightward shifted in the cells transfected with p.A287Lfs*193. Variants of the LMNA gene caused significant reduction of the peak INa in HEK-293 cells, which may account for the patients’ AVB.

Keywords

Lamin A/C; atrioventricular block; cardiomyopathy; sodium channel.

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Submitted: 2017-10-07 04:35:31
Published: 2018-02-22 10:52:33
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Copyright (c) 2018 Michael A. Olaopa, Katherine G. Spoonamore, Deepak Bhakta, Zhenhui Chen, Patricia B.S. Celestino-Soper, Peng-Sheng Chen, Tomohiko Ai, Matteo Vatta

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