title: N- and C-terminal KCNE1 mutations cause distinct phenotypes of long QT syndrome.
abstract: BACKGROUND
  Long QT syndromes (LQTS) are inherited diseases involving mutations to genes encoding a number of cardiac ion channels and a membrane adaptor protein. The MinK protein is a cardiac K-channel accessory subunit encoded by the KCNE1 gene, mutations of which are associated with the LQT5 form of LQTS.
  
  
  OBJECTIVE
  The purpose of this study was to search for the KCNE1 mutations and clarify the function of those mutations.
  
  
  METHODS
  We conducted a genetic screen of KCNE1 mutations in 151 Japanese LQTS patients using the denaturing high-performance liquid chromatography-WAVE system and direct sequencing. In two LQTS patients, we identified two KCNE1 missense mutations, located in the MinK N- and C-terminal domains. The functional effects of these mutations were examined by heterologous coexpression with KCNQ1 and KCNH2.
  
  
  RESULTS
  One mutation, which was identified in a 67-year-old woman, A8V, was novel. Her electrocardiogram (ECG) revealed marked bradycardia and QT interval prolongation. Another mutation, R98W, was identified in a 19-year-old woman. She experienced syncope followed by palpitation in exercise. At rest, her ECG showed bradycardia with mild QT prolongation, which became more prominent during exercise. In electrophysiological analyses, R98W produced reduced I(Ks) currents with a positive shift in the half activation voltages. In addition, when the A8V mutation was coexpressed with KCNH2, this reduced current magnitude, which is suggestive of a modifier effect by the A8V KCNE1 mutation on I(Kr).
  
  
  CONCLUSIONS
  KCNE1 mutations may be associated with mild LQTS phenotypes, and KCNE1 gene screening is of clinical importance for asymptomatic and mild LQTS patients.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.forename: Dimitar P
authors.initials: DP
authors.lastname: Zankov
authors.forename: Hidetada
authors.initials: H
authors.lastname: Yoshida
authors.forename: Keiko
authors.initials: K
authors.lastname: Tsuji
authors.forename: Takeru
authors.initials: T
authors.lastname: Makiyama
authors.forename: Hideki
authors.initials: H
authors.lastname: Itoh
authors.forename: Masaharu
authors.initials: M
authors.lastname: Akao
authors.forename: Jules C
authors.initials: JC
authors.lastname: Hancox
authors.forename: Toru
authors.initials: T
authors.lastname: Kita
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000235:genetics; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007564:Japan; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008133:Long QT Syndrome / Q000235:genetics*; D020125:Mutation, Missense; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*; D012107:Research Design
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C489622:KCNE1 protein, human; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D024642:Potassium Channels, Voltage-Gated