title: A novel mutation in the SCN5A gene contributes to arrhythmogenic characteristics of early repolarization syndrome.
abstract: Several genetic variants have been associated with early repolarization syndrome (ERS). However, the lack of functional validations of the mutant effects has limited the interpretation of genetic tests. In the present study, we identified and characterized a novel sodium channel, voltage gated, type V alpha subunit (SCN5A) mutation that was associated with ERS. A 67-year-old male proband suffering from recurrent syncope underwent a documented electrocardiogram (ECG) for polymorphic ventricular tachycardia (VT). It was noted that baseline 12-lead ECG exhibited a predominantly elevated ST-segment which mimicked acute myocardial ischemia in lead V2-V6, and the ECG also demonstrated J waves in lead Ⅱ, Ⅲ, aVF and V2-V6. Using genetic analysis, we noted that the proband carried a novel heterozygous missense mutation of A1055G in the SCN5A gene. Whole-cell configuration of patch-clamp analysis revealed that the mutation significantly decreased peak sodium current (INa) density and shifted the steady-state inactivation curve of INa to a more negative potential. Confocal imaging suggested that in the mutant channel a defect of protein expression both on the cell membrane and in cytoplasm was present. The present study demonstrated that a novel heterozygous missense mutation of A1055G in SCN5A led to 'loss-of function' of the sodium channels, and we suggest that it accounts for the arrhythmogenic characteristics of ERS.
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, P.R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, P.R. China.
authors.forename: Lan
authors.initials: L
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, P.R. China.
authors.forename: Xuhua
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, P.R. China.
authors.forename: Cuihong
authors.initials: C
authors.lastname: Hou
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, P.R. China.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Chu
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, P.R. China.
authors.forename: Jielin
authors.initials: J
authors.lastname: Pu
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, P.R. China.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000368:Aged; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D053840:Brugada Syndrome / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D000075224:Cardiac Conduction System Disease; D016757:Death, Sudden, Cardiac / Q000209:etiology / Q000473:pathology; D004562:Electrocardiography; D020022:Genetic Predisposition to Disease / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D018408:Patch-Clamp Techniques
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human
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