title: Identification and characterization of a novel genetic mutation with prolonged QT syndrome in an unexplained postoperative death.
abstract: BACKGROUND
  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).
  
  
  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.
  
  
  CONCLUSIONS
  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).
authors.affiliation: Department of Legal Medicine, Faculty of Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hata
authors.forename: Hisashi
authors.initials: H
authors.lastname: Mori
authors.forename: Ayumi
authors.initials: A
authors.lastname: Tanaka
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Fujita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimomura
authors.forename: Toshihide
authors.initials: T
authors.lastname: Tabata
authors.forename: Koshi
authors.initials: K
authors.lastname: Kinoshita
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Fukiko
authors.initials: F
authors.lastname: Ichida
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kominato
authors.forename: Noriaki
authors.initials: N
authors.lastname: Ikeda
authors.forename: Naoki
authors.initials: N
authors.lastname: Nishida
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000473:pathology*; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening; D006102:Granuloma, Laryngeal / Q000473:pathology / Q000601:surgery; D006801:Humans; D007828:Laryngoscopy; D008133:Long QT Syndrome / Q000235:genetics* / Q000473:pathology*; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D009206:Myocardium / Q000473:pathology; D011110:Polymorphism, Genetic / Q000235:genetics; D011183:Postoperative Complications / Q000235:genetics* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D012333:RNA, Messenger
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