KCNE5 (KCNE1L) Variants Are Novel Modulators of Brugada Syndrome and Idiopathic Ventricular Fibrillation

• Published in: Circulation. Arrhythmia and electrophysiology Vol. 4; no. 3; pp. 352 - 361
• Main Authors: Ohno, Seiko, Zankov, Dimitar P, Ding, Wei-Guang, Itoh, Hideki, Makiyama, Takeru, Doi, Takahiro, Shizuta, Satoshi, Hattori, Tetsuhisa, Miyamoto, Akashi, Naiki, Nobu, Hancox, Jules C, Matsuura, Hiroshi, Horie, Minoru
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.06.2011
• Subjects: Adult; Brugada Syndrome - genetics; Brugada Syndrome - metabolism; Brugada Syndrome - physiopathology; Cell Line; Computer Simulation; DNA - genetics; Female; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Mutation; Myocardium - metabolism; Myocardium - pathology; Patch-Clamp Techniques; Pedigree; Polymerase Chain Reaction; Potassium Channels, Voltage-Gated - genetics; Potassium Channels, Voltage-Gated - metabolism; Ventricular Fibrillation - genetics; Ventricular Fibrillation - metabolism; Ventricular Fibrillation - physiopathology
• ISSN: 1941-3149; 1941-3084
• DOI: 10.1161/CIRCEP.110.959619

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 (Ito), 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). METHODS AND 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 variantsp.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, Ito 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 Ito, and its novel variants appeared to cause IVF, especially BrS, in male patients through gain-of-function effects on Ito. Screening for KCNE5 variants is relevant for BrS or IVF.