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

  • 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 | ait@iu.edu 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.
  • 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.

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Published
2018-02-22
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Original Articles
Supporting Agencies
Peng Sheng Chen, 1P01 HL78931, R01 HL71140, R42DA043391, Tomohiko Ai, Methodist Research Institute, Showalter Cardiovascular Research Fund, Matteo Vatta, Patricia BS Celestino Soper, Indiana University Health–Indiana Uni
Keywords:
Lamin A/C, atrioventricular block, cardiomyopathy, sodium channel.
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How to Cite
Olaopa, M. A., Spoonamore, K. G., Bhakta, D., Chen, Z., Celestino-Soper, P. B., Chen, P.-S., Ai, T., & Vatta, M. (2018). Lamin-A/C variants found in patients with cardiac conduction disease reduce sodium currents. Cardiogenetics, 8(1). https://doi.org/10.4081/cardiogenetics.2018.7127