title: KCNE5 (KCNE1L) variants are novel modulators of Brugada syndrome and idiopathic ventricular fibrillation.
abstract: BACKGROUND
  Brugada syndrome (BrS) has a significantly higher incidence among the male sex. Among genes coding ion channels and their modulatory proteins, KCNE5 (KCNE1L) is located in the X chromosome and encodes an auxiliary β-subunit for K channels. KCNE5 has been shown to modify the transient outward current (I(to)), which plays a key role in determining the repolarization process in the myocardium. This study investigated whether KCNE5 mutations could be responsible for BrS and other idiopathic ventricular fibrillation (IVF).
  
  
  RESULTS
  In 205 Japanese patients with BrS or IVF who tested negative for SCN5A mutation, we conducted a genetic screen for KCNE5 variants. We identified 2 novel KCNE5 variants: p.Y81H in 3 probands and p.[D92E;E93X] in 1 proband from 4 unrelated families. Y81H was identified in 1 man and 2 women; D92E;E93X was found in a 59-year-old man. All probands received implantable cardioverter-defibrillators. Functional consequences of the KCNE5 variants were determined through biophysical assay using cotransfection with KCND3 or KCNQ1. In the experiments with KCND3, which encodes Kv4.3, I(to) was significantly increased for both KCNE5 variants compared to wild type. In contrast, there were no significant changes in current properties reconstructed by KCNQ1+ wild type KCNE5 and the 2 variants. With the simulation model, both variants demonstrated notch-and-dome or loss-of-dome patterns.
  
  
  CONCLUSIONS
  KCNE5 modulates I(to), and its novel variants appeared to cause IVF, especially BrS, in male patients through gain-of-function effects on I(to). Screening for KCNE5 variants is relevant for BrS or IVF.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.forename: Dimitar P
authors.initials: DP
authors.lastname: Zankov
authors.forename: Wei-Guang
authors.initials: WG
authors.lastname: Ding
authors.forename: Hideki
authors.initials: H
authors.lastname: Itoh
authors.forename: Takeru
authors.initials: T
authors.lastname: Makiyama
authors.forename: Takahiro
authors.initials: T
authors.lastname: Doi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shizuta
authors.forename: Tetsuhisa
authors.initials: T
authors.lastname: Hattori
authors.forename: Akashi
authors.initials: A
authors.lastname: Miyamoto
authors.forename: Nobu
authors.initials: N
authors.lastname: Naiki
authors.forename: Jules C
authors.initials: JC
authors.lastname: Hancox
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuura
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D000328:Adult; D053840:Brugada Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002460:Cell Line; D003198:Computer Simulation; D004247:DNA / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018408:Patch-Clamp Techniques; D010375:Pedigree; D016133:Polymerase Chain Reaction; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics* / Q000378:metabolism; D014693:Ventricular Fibrillation / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
chemical_list: C502068:KCNE5 protein, human; D024642:Potassium Channels, Voltage-Gated; D004247:DNA