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Hereditary aspects of AF, however, remain not fully elucidated. Objective: The purpose of this study was to identify genetic backgrounds contributed to juvenile-onset AF and to define the mechanism. Methods: In 30 consecutive juvenile-onset AF patients (onset age \u003c50 year-old), we screened AF-related genes (KCNQ1, KCNH2, KCNE1-3 and 5, KCNJ2, and SCN5A). We analyzed the function of mutant channels using whole-cell patch-clamp techniques and computer simulations. Results: Among the juvenile-onset AF patients, we identified three mutations (10%), SCN5A-M1875T, KCNJ2-M301K, and KCNQ1-G229D. Since KCNQ1 variant (G229) identified in a 16-year-old boy was novel, we focused on the proband. The G229D-IKs was found to induce a large instantaneous activating component without deactivation after repolarization to –50 mV. In addition, WT/G229D-IKs (WT and mutant co-expression) displayed both instantaneous and time-dependent activating currents. Compared to WT-IKs, the tail current densities in WT/G229D-IKs were larger at test potentials between –130 and –40 mV, but smaller at test potentials between 20 and 50 mV. Moreover, WT/G229D-IKs resulted in a negative voltage shift for current activation (−35.2 mV) and slower deactivation. WT/G229D-IKs conducted a large outward current Hasegawa et al. A novel KCNQ1 mutation in Juvenile-Onset AF 4 induced by an atrial action potential waveform, and computer simulation incorporating the WT/G229D-IKs results revealed that the mutation shortened atrial but not ventricular action potential. 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A Novel KCNQ1 Missense Mutation Identified in a Patient with Juvenile-Onset Atrial Fibrillation Causes Constitutively Open IKs Channels
http://hdl.handle.net/10191/27327
http://hdl.handle.net/10191/2732789eb714d-ab1d-48fe-a817-2f9259f495a4
名前 / ファイル | ライセンス | アクション |
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本文 (1.7 MB)
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要旨 (202.0 kB)
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Item type | 学位論文 / Thesis or Dissertation(1) | |||||
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公開日 | 2014-05-22 | |||||
タイトル | ||||||
タイトル | A Novel KCNQ1 Missense Mutation Identified in a Patient with Juvenile-Onset Atrial Fibrillation Causes Constitutively Open IKs Channels | |||||
タイトル | ||||||
言語 | en | |||||
タイトル | A Novel KCNQ1 Missense Mutation Identified in a Patient with Juvenile-Onset Atrial Fibrillation Causes Constitutively Open IKs Channels | |||||
言語 | ||||||
言語 | eng | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | atrial fibrillation | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | juvenile-onset atrial fibrillation | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | ion channel | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | Iks | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | KCNQ1 | |||||
資源タイプ | ||||||
資源 | http://purl.org/coar/resource_type/c_46ec | |||||
タイプ | thesis | |||||
その他のタイトル | ||||||
その他のタイトル | 若年性心房細動患者に同定された新たなKCNQ1ミスセンス変異はIKsチャネルを持続的に開口させる | |||||
著者 |
Hasegawa, Kanae
× Hasegawa, Kanae |
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著者別名 | ||||||
識別子 | 50259 | |||||
識別子Scheme | WEKO | |||||
姓名 | 長谷川, 奏恵 | |||||
抄録 | ||||||
内容記述タイプ | Abstract | |||||
内容記述 | Background: Atrial fibrillation (AF) is one of the most common cardiac arrhythmias, and in some patients, the disease is inheritable. Hereditary aspects of AF, however, remain not fully elucidated. Objective: The purpose of this study was to identify genetic backgrounds contributed to juvenile-onset AF and to define the mechanism. Methods: In 30 consecutive juvenile-onset AF patients (onset age <50 year-old), we screened AF-related genes (KCNQ1, KCNH2, KCNE1-3 and 5, KCNJ2, and SCN5A). We analyzed the function of mutant channels using whole-cell patch-clamp techniques and computer simulations. Results: Among the juvenile-onset AF patients, we identified three mutations (10%), SCN5A-M1875T, KCNJ2-M301K, and KCNQ1-G229D. Since KCNQ1 variant (G229) identified in a 16-year-old boy was novel, we focused on the proband. The G229D-IKs was found to induce a large instantaneous activating component without deactivation after repolarization to –50 mV. In addition, WT/G229D-IKs (WT and mutant co-expression) displayed both instantaneous and time-dependent activating currents. Compared to WT-IKs, the tail current densities in WT/G229D-IKs were larger at test potentials between –130 and –40 mV, but smaller at test potentials between 20 and 50 mV. Moreover, WT/G229D-IKs resulted in a negative voltage shift for current activation (−35.2 mV) and slower deactivation. WT/G229D-IKs conducted a large outward current Hasegawa et al. A novel KCNQ1 mutation in Juvenile-Onset AF 4 induced by an atrial action potential waveform, and computer simulation incorporating the WT/G229D-IKs results revealed that the mutation shortened atrial but not ventricular action potential. Conclusion: A novel KCNQ1-G229D mutation identified in a juvenile-onset AF patient altered the IKs activity and kinetics, thereby increasing the arrhythmogenicity to AF. | |||||
内容記述 | ||||||
内容記述タイプ | Other | |||||
内容記述 | 学位の種類: 博士(医学). 報告番号: 甲第3861号. 学位記番号: 新大院博(医)甲第601号. 学位授与年月日: 平成26年3月24日 | |||||
内容記述 | ||||||
内容記述タイプ | Other | |||||
内容記述 | Heart Rhythm. 2014, 11(1), 67-75 | |||||
書誌情報 | p. 1-30, 発行日 2014-03-24 | |||||
出版者 | ||||||
出版者 | 新潟大学 | |||||
DOI | ||||||
識別子タイプ | DOI | |||||
関連識別子 | info:doi/10.1016/j.hrthm.2013.09.073 | |||||
権利 | ||||||
権利情報 | Copyright (C) 2013 Elsevier | |||||
著者版フラグ | ||||||
値 | ETD | |||||
学位名 | ||||||
学位名 | 博士(医学) | |||||
学位授与機関 | ||||||
学位授与機関名 | 新潟大学 | |||||
学位授与年月日 | ||||||
学位授与年月日 | 2014-03-24 | |||||
学位授与番号 | ||||||
学位授与番号 | 13101甲第3861号 | |||||
学位記番号 | ||||||
内容記述タイプ | Other | |||||
内容記述 | 新大院博(医)甲第601号 |