title: Gain-of-function KCNH2 mutations in patients with Brugada syndrome.
abstract: BACKGROUND
  Brugada syndrome (BrS) is an inherited disease characterized by right precordial ST segment elevation on electrocardiograms (ECGs) that predisposes patients to sudden cardiac death as a result of polymorphic ventricular tachyarrhythmia or ventricular fibrillation (VF). In BrS patients, except for SCN5A, mutations in other responsible genes are poorly elucidated.
  
  
  RESULTS
  We identified 4 KCNH2 mutations, T152I, R164C, W927G, and R1135H, in 236 consecutive probands with BrS or Brugada-like ECG. Three of these mutation carriers showed QTc intervals shorter than 360 milliseconds and 1 experienced VF. We performed patch-clamp analyses on I(Kr) reconstituted with the KCNH2 mutations in Chinese hamster ovary cells and compared the phenotypes of the patients with different genotypes. Three mutations, R164C, W927G, and R1135H, increased I(Kr) densities. Three mutations, T152I, R164C, and W927G, caused a negative shift in voltage-dependent activation curves. Only the R1135H mutant channel prolonged the deactivation time constants. We also identified 20 SCN5A and 5 CACNA1C mutation carriers in our cohort. Comparison of probands' phenotypes with 3 different genotypes revealed that KCNH2 mutation carriers showed shorter QTc intervals and SCN5A mutation carriers had longer QRS durations.
  
  
  CONCLUSIONS
  All KCNH2 mutations that we identified in probands with BrS exerted gain-of-function effects on I(Kr) channels, which may partially explain the ECG findings in our patients.
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Q I
authors.initials: QI
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.affiliation: Division of Physiology, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Wei-Guang
authors.initials: WG
authors.lastname: Ding
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Fukuyama
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Akashi
authors.initials: A
authors.lastname: Miyamoto
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Itoh
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Makiyama
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: Division of Physiology, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Bai
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Kanae
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University Faculty of Medicine, Yufu, Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Shinohara
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University Faculty of Medicine, Yufu, Japan.
authors.forename: Naohiko
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Faculty of Health Sciences, Yamaguchi Graduate School of Medicine, Ube, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Shimizu
authors.affiliation: Division of Physiology, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuura
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D000200:Action Potentials; D000328:Adult; D000818:Animals; D053840:Brugada Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D016466:CHO Cells; D020746:Calcium Channels, L-Type / Q000235:genetics; D003412:Cricetulus; D004252:DNA Mutational Analysis; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics; D018408:Patch-Clamp Techniques; D010641:Phenotype; D011379:Prognosis; D014162:Transfection
chemical_list: C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human
keywords: Brugada syndrome; KCNH2; mutation; patch-clamp; ventricular tachycardia