A Novel KCNQ1 Missense Mutation Identified in a Patient with Juvenile-Onset Atrial Fibrillation Causes Constitutively Open IKs Channels

• Material Type: 博士論文
• Title: A Novel KCNQ1 Missense Mutation Identified in a Patient with Juvenile-Onset Atrial Fibrillation Causes Constitutively Open IKs Channels
• Author/Editor: Hasegawa, Kanae
• Publication, Distribution, etc.: 新潟大学
• Publication Date: 2014-03-24
• Publication Date (W3CDTF): 2014-03-24
• Alternative Title: A Novel KCNQ1 Missense Mutation Identified in a Patient with Juvenile-Onset Atrial Fibrillation Causes Constitutively Open IKs Channels; 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
• Degree grantor/type: 新潟大学
• Date Granted: 2014-03-24
• Date Granted (W3CDTF): 2014-03-24
• Dissertation Number: 甲第3861号
• Degree Type: 博士（医学）
• Conferring No. (Dissertation): 甲第3861号
• Text Language Code: eng
• Subject Heading: atrial fibrillation; juvenile-onset atrial fibrillation; ion channel; Iks; KCNQ1
• Note (General): 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.; 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; Heart Rhythm. 2014, 11(1), 67-75; 新大院博（医）甲第601号; 元資料の権利情報 : Copyright (C) 2013 Elsevier; 開始ページ : 1; 終了ページ : 30
• DOI: info:doi/10.1016/j.hrthm.2013.09.073; https://doi.org/info:doi/10.1016/j.hrthm.2013.09.073
• Persistent ID (NDL): info:ndljp/pid/8949846; https://dl.ndl.go.jp/pid/8949846
• Collection: 障害者向け資料
• Collection (Materials For Handicapped People:1): テキストデータ
• Collection (particular): 国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文; https://dl.ndl.go.jp/collections/A00014
• Acquisition Basis: 博士論文（自動収集）
• Available (W3CDTF): 2015-03-03
• Date Accepted (W3CDTF): 2015-02-03T05:25:05+09:00
• Date Created (W3CDTF): 2019-08-05
• Format (IMT): application/pdf
• Access Restrictions: 国立国会図書館内限定公開
• Service for the Digitized Contents Transmission Service: 図書館・個人送信対象外
• Availability of remote photoduplication service: 可
• Periodical Title (URI): http://hdl.handle.net/10191/27327
• Data Provider (Database): 国立国会図書館 : 国立国会図書館デジタルコレクション; https://dl.ndl.go.jp