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

Research output: Contribution to journalArticle

6 Citations (Scopus)

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(â̂†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).

Original languageEnglish
Pages (from-to)105-115
Number of pages11
JournalInternational Journal of Legal Medicine
Volume128
Issue number1
DOIs
Publication statusPublished - Jan 1 2014

Fingerprint

Ether
Mutation
Genes
Long QT Syndrome
HEK293 Cells
T-Lymphocytes
Frameshift Mutation
Proteins
Potassium Channels
Sudden Cardiac Death
Missense Mutation
Immunoblotting
Virulence
Molecular Biology

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Identification and characterization of a novel genetic mutation with prolonged QT syndrome in an unexplained postoperative death. / Hata, Yukiko; Mori, Hisashi; Tanaka, Ayumi; Fujita, Yosuke; Shimomura, Takeshi; Tabata, Toshihide; Kinoshita, Koshi; Yamaguchi, Yoshiaki; Ichida, Fukiko; Kominato, Yoshihiko; Ikeda, Noriaki; Nishida, Naoki.

In: International Journal of Legal Medicine, Vol. 128, No. 1, 01.01.2014, p. 105-115.

Research output: Contribution to journalArticle

Hata, Y, Mori, H, Tanaka, A, Fujita, Y, Shimomura, T, Tabata, T, Kinoshita, K, Yamaguchi, Y, Ichida, F, Kominato, Y, Ikeda, N & Nishida, N 2014, 'Identification and characterization of a novel genetic mutation with prolonged QT syndrome in an unexplained postoperative death', International Journal of Legal Medicine, vol. 128, no. 1, pp. 105-115. https://doi.org/10.1007/s00414-013-0853-4
Hata, Yukiko ; Mori, Hisashi ; Tanaka, Ayumi ; Fujita, Yosuke ; Shimomura, Takeshi ; Tabata, Toshihide ; Kinoshita, Koshi ; Yamaguchi, Yoshiaki ; Ichida, Fukiko ; Kominato, Yoshihiko ; Ikeda, Noriaki ; Nishida, Naoki. / Identification and characterization of a novel genetic mutation with prolonged QT syndrome in an unexplained postoperative death. In: International Journal of Legal Medicine. 2014 ; Vol. 128, No. 1. pp. 105-115.
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abstract = "Introduction: The human ether-{\`a}-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({\^a}̂†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).",
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AU - Hata, Yukiko

AU - Mori, Hisashi

AU - Tanaka, Ayumi

AU - Fujita, Yosuke

AU - Shimomura, Takeshi

AU - Tabata, Toshihide

AU - Kinoshita, Koshi

AU - Yamaguchi, Yoshiaki

AU - Ichida, Fukiko

AU - Kominato, Yoshihiko

AU - Ikeda, Noriaki

AU - Nishida, Naoki

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N2 - 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(â̂†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).

AB - 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(â̂†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).

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