<i>KCNE5</i> ( <i>KCNE1L</i> ) Variants Are Novel Modulators of Brugada Syndrome and Idiopathic Ventricular Fibrillation
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- Seiko Ohno
- From the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (S.O., T.M., T.D., S.S., T.H.); Department of Physiology (D.P.Z., W.-G.D., H.M.) and Department of Cardiovascular and Respiratory Medicine (D.P.Z., H.I., A.M., N.N., M.H.), Shiga University of Medical Science, Otsu, Japan; and Department of Physiology, School of Medical Sciences, University of Bristol, Bristol, UK (J.C.H.).
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- Dimitar P. Zankov
- From the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (S.O., T.M., T.D., S.S., T.H.); Department of Physiology (D.P.Z., W.-G.D., H.M.) and Department of Cardiovascular and Respiratory Medicine (D.P.Z., H.I., A.M., N.N., M.H.), Shiga University of Medical Science, Otsu, Japan; and Department of Physiology, School of Medical Sciences, University of Bristol, Bristol, UK (J.C.H.).
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- Wei-Guang Ding
- From the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (S.O., T.M., T.D., S.S., T.H.); Department of Physiology (D.P.Z., W.-G.D., H.M.) and Department of Cardiovascular and Respiratory Medicine (D.P.Z., H.I., A.M., N.N., M.H.), Shiga University of Medical Science, Otsu, Japan; and Department of Physiology, School of Medical Sciences, University of Bristol, Bristol, UK (J.C.H.).
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- Hideki Itoh
- From the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (S.O., T.M., T.D., S.S., T.H.); Department of Physiology (D.P.Z., W.-G.D., H.M.) and Department of Cardiovascular and Respiratory Medicine (D.P.Z., H.I., A.M., N.N., M.H.), Shiga University of Medical Science, Otsu, Japan; and Department of Physiology, School of Medical Sciences, University of Bristol, Bristol, UK (J.C.H.).
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- Takeru Makiyama
- From the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (S.O., T.M., T.D., S.S., T.H.); Department of Physiology (D.P.Z., W.-G.D., H.M.) and Department of Cardiovascular and Respiratory Medicine (D.P.Z., H.I., A.M., N.N., M.H.), Shiga University of Medical Science, Otsu, Japan; and Department of Physiology, School of Medical Sciences, University of Bristol, Bristol, UK (J.C.H.).
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- Takahiro Doi
- From the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (S.O., T.M., T.D., S.S., T.H.); Department of Physiology (D.P.Z., W.-G.D., H.M.) and Department of Cardiovascular and Respiratory Medicine (D.P.Z., H.I., A.M., N.N., M.H.), Shiga University of Medical Science, Otsu, Japan; and Department of Physiology, School of Medical Sciences, University of Bristol, Bristol, UK (J.C.H.).
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- Satoshi Shizuta
- From the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (S.O., T.M., T.D., S.S., T.H.); Department of Physiology (D.P.Z., W.-G.D., H.M.) and Department of Cardiovascular and Respiratory Medicine (D.P.Z., H.I., A.M., N.N., M.H.), Shiga University of Medical Science, Otsu, Japan; and Department of Physiology, School of Medical Sciences, University of Bristol, Bristol, UK (J.C.H.).
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- Tetsuhisa Hattori
- From the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (S.O., T.M., T.D., S.S., T.H.); Department of Physiology (D.P.Z., W.-G.D., H.M.) and Department of Cardiovascular and Respiratory Medicine (D.P.Z., H.I., A.M., N.N., M.H.), Shiga University of Medical Science, Otsu, Japan; and Department of Physiology, School of Medical Sciences, University of Bristol, Bristol, UK (J.C.H.).
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- Akashi Miyamoto
- From the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (S.O., T.M., T.D., S.S., T.H.); Department of Physiology (D.P.Z., W.-G.D., H.M.) and Department of Cardiovascular and Respiratory Medicine (D.P.Z., H.I., A.M., N.N., M.H.), Shiga University of Medical Science, Otsu, Japan; and Department of Physiology, School of Medical Sciences, University of Bristol, Bristol, UK (J.C.H.).
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- Nobu Naiki
- From the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (S.O., T.M., T.D., S.S., T.H.); Department of Physiology (D.P.Z., W.-G.D., H.M.) and Department of Cardiovascular and Respiratory Medicine (D.P.Z., H.I., A.M., N.N., M.H.), Shiga University of Medical Science, Otsu, Japan; and Department of Physiology, School of Medical Sciences, University of Bristol, Bristol, UK (J.C.H.).
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- Jules C. Hancox
- From the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (S.O., T.M., T.D., S.S., T.H.); Department of Physiology (D.P.Z., W.-G.D., H.M.) and Department of Cardiovascular and Respiratory Medicine (D.P.Z., H.I., A.M., N.N., M.H.), Shiga University of Medical Science, Otsu, Japan; and Department of Physiology, School of Medical Sciences, University of Bristol, Bristol, UK (J.C.H.).
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- Hiroshi Matsuura
- From the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (S.O., T.M., T.D., S.S., T.H.); Department of Physiology (D.P.Z., W.-G.D., H.M.) and Department of Cardiovascular and Respiratory Medicine (D.P.Z., H.I., A.M., N.N., M.H.), Shiga University of Medical Science, Otsu, Japan; and Department of Physiology, School of Medical Sciences, University of Bristol, Bristol, UK (J.C.H.).
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- Minoru Horie
- From the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (S.O., T.M., T.D., S.S., T.H.); Department of Physiology (D.P.Z., W.-G.D., H.M.) and Department of Cardiovascular and Respiratory Medicine (D.P.Z., H.I., A.M., N.N., M.H.), Shiga University of Medical Science, Otsu, Japan; and Department of Physiology, School of Medical Sciences, University of Bristol, Bristol, UK (J.C.H.).
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説明
<jats:sec> <jats:title>Background—</jats:title> <jats:p> Brugada syndrome (BrS) has a significantly higher incidence among the male sex. Among genes coding ion channels and their modulatory proteins, <jats:italic>KCNE5</jats:italic> ( <jats:italic>KCNE1L</jats:italic> ) 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 <jats:sub>to</jats:sub> ), which plays a key role in determining the repolarization process in the myocardium. This study investigated whether <jats:italic>KCNE5</jats:italic> mutations could be responsible for BrS and other idiopathic ventricular fibrillation (IVF). </jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p> In 205 Japanese patients with BrS or IVF who tested negative for <jats:italic>SCN5A</jats:italic> mutation, we conducted a genetic screen for <jats:italic>KCNE5</jats:italic> variants. We identified 2 novel <jats:italic>KCNE5</jats:italic> 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 <jats:italic>KCNE5</jats:italic> variants were determined through biophysical assay using cotransfection with <jats:italic>KCND3</jats:italic> or <jats:italic>KCNQ1</jats:italic> . In the experiments with <jats:italic>KCND3</jats:italic> , which encodes Kv4.3, I <jats:sub>to</jats:sub> was significantly increased for both <jats:italic>KCNE5</jats:italic> variants compared to wild type. In contrast, there were no significant changes in current properties reconstructed by <jats:italic>KCNQ1</jats:italic> + wild type <jats:italic>KCNE5</jats:italic> and the 2 variants. With the simulation model, both variants demonstrated notch-and-dome or loss-of-dome patterns. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p> KCNE5 modulates I <jats:sub>to</jats:sub> , and its novel variants appeared to cause IVF, especially BrS, in male patients through gain-of-function effects on I <jats:sub>to</jats:sub> . Screening for <jats:italic>KCNE5</jats:italic> variants is relevant for BrS or IVF. </jats:p> </jats:sec>
収録刊行物
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- Circulation: Arrhythmia and Electrophysiology
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Circulation: Arrhythmia and Electrophysiology 4 (3), 352-361, 2011-06
Ovid Technologies (Wolters Kluwer Health)