International Journal of Legal Medicine

, Volume 128, Issue 1, pp 105–115

Identification and characterization of a novel genetic mutation with prolonged QT syndrome in an unexplained postoperative death

  • Yukiko Hata
  • Hisashi Mori
  • Ayumi Tanaka
  • Yosuke Fujita
  • Takeshi Shimomura
  • Toshihide Tabata
  • Koshi Kinoshita
  • Yoshiaki Yamaguchi
  • Fukiko Ichida
  • Yoshihiko Kominato
  • Noriaki Ikeda
  • Naoki Nishida
Original Article

Abstract

Introduction

The human ether-à-go-go-related gene (hERG) encodes the α-subunit of a cardiac potassium channel. Various mutations of hERG, including missense mutations, have been reported to cause long QT syndrome (LQTS) and severe arrhythmic disorders such as sudden cardiac death. We identified a novel hERG frameshift mutation (hERG(ΔAT)) in the S5-pore region from a LQTS patient who died suddenly and analyzed its genetic profile and the molecular and electrophysiological behaviors of the protein product to assess the pathogenicity of hERG(ΔAT).

Methods and results

We performed direct sequencing of hERG and evaluated its transcript level by using a whole blood sample from the patient. We performed immunoblotting, immunocytochemistry, and patch-clamp recordings of HEK-293 T cells transfected with hERG(ΔAT), wild-type hERG (hERG(WT)), or both. The patient demonstrated an AT deletion (c.1735_1736del) in hERG and a decrease in hERG mRNA transcripts. HEK-293 T cells showed lower production and cell surface expression of hERG(ΔAT) compared with hERG(WT) protein. In addition, the hERG(∆AT) protein failed to form functional channels, while the activation kinetics of functional channels, presumably consisting of hERG(WT) subunits, were unaffected.

Conclusion

The ΔAT mutation may decrease the number of functional hERG channels by impairing the posttranscriptional and posttranslational processing of the mutant product. This decrease may partly explain the cardiac symptoms of the patient who was heterozygous for hERG(ΔAT).

Keywords

M579fs + 75X frameshift mutation Human ether-à-go-go-related gene Long QT syndrome Patch-clamp Transmembrane pore domain Arrhythmia 

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Yukiko Hata
    • 1
  • Hisashi Mori
    • 2
  • Ayumi Tanaka
    • 2
  • Yosuke Fujita
    • 3
  • Takeshi Shimomura
    • 3
  • Toshihide Tabata
    • 3
  • Koshi Kinoshita
    • 1
  • Yoshiaki Yamaguchi
    • 4
  • Fukiko Ichida
    • 5
  • Yoshihiko Kominato
    • 6
  • Noriaki Ikeda
    • 7
  • Naoki Nishida
    • 1
  1. 1.Department of Legal Medicine, Faculty of Medicine, Graduate School of Medicine and Pharmaceutical Sciences for ResearchUniversity of ToyamaToyamaJapan
  2. 2.Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences for ResearchUniversity of ToyamaToyamaJapan
  3. 3.Laboratory for Neural Information Technology, Graduate School of Sciences and EngineeringUniversity of ToyamaToyamaJapan
  4. 4.Second Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Sciences for ResearchUniversity of ToyamaToyamaJapan
  5. 5.Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences for ResearchUniversity of ToyamaToyamaJapan
  6. 6.Department of Legal Medicine, Graduate School of MedicineGunma UniversityMaebashiJapan
  7. 7.Department of Forensic Pathology and Sciences, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan

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