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 journalArticlepeer-review

7 Citations (Scopus)


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
Issue number1
Publication statusPublished - Jan 2014

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine


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