International Journal of Legal Medicine

, Volume 128, Issue 1, pp 105–115 | Cite as

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 NishidaEmail author
Original Article



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.


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).


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



We thank Drs. Kenshi Hayashi (Kanazawa University Graduate School of Medical Science, Kanazawa, Japan), Sabina Kupershmidt (Vanderbilt University School of Medicine, Nashville, USA), and Jun-ichi Miyazaki (Osaka University Medical School, Osaka, Japan) for providing plasmids. We also thank Prof. K. Fukurotani for the opportunity to perform this work. This work was supported in part by KAKENHI grants from MEXT, Japan, to T.T. (19045019, 20022025, 20500284, 21026011, and 23500384) and a KAKENHI grant from JSPS, Japan, to Y.H. (24590852).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics statement

The experiments described in this manuscript conform to the Declaration of Helsinki, and the protocols of gene sampling and manipulation were approved by the University of Toyama’s committee on the usage of human genetic material (#24-1).


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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
    Email author
  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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