PubMed:29506689 JSONTXT

{"project":"kaiyin_test","denotations":[{"id":"T1","span":{"begin":83,"end":105},"obj":"Disease"},{"id":"T2","span":{"begin":118,"end":124},"obj":"Gene"},{"id":"T3","span":{"begin":125,"end":141},"obj":"PosReg"},{"id":"T19","span":{"begin":152,"end":157},"obj":"Var"},{"id":"T5","span":{"begin":178,"end":187},"obj":"Var"},{"id":"T6","span":{"begin":192,"end":199},"obj":"Reg"},{"id":"T7","span":{"begin":210,"end":226},"obj":"Disease"},{"id":"T9","span":{"begin":667,"end":672},"obj":"Gene"},{"id":"T8","span":{"begin":689,"end":706},"obj":"Var"},{"id":"T10","span":{"begin":781,"end":793},"obj":"Reg"},{"id":"T20","span":{"begin":847,"end":852},"obj":"Var"},{"id":"T12","span":{"begin":1605,"end":1611},"obj":"Gene"},{"id":"T21","span":{"begin":1612,"end":1617},"obj":"Var"},{"id":"T15","span":{"begin":1648,"end":1664},"obj":"PosReg"},{"id":"T18","span":{"begin":1721,"end":1743},"obj":"Disease"}],"relations":[{"id":"R15","pred":"ThemeOf","subj":"T2","obj":"T19"},{"id":"R16","pred":"CauseOf","subj":"T19","obj":"T3"},{"id":"R17","pred":"ThemeOf","subj":"T20","obj":"T10"},{"id":"R18","pred":"ThemeOf","subj":"T12","obj":"T21"},{"id":"R19","pred":"CauseOf","subj":"T21","obj":"T15"},{"id":"R20","pred":"ThemeOf","subj":"T18","obj":"T15"},{"id":"R3","pred":"ThemeOf","subj":"T1","obj":"T3"},{"id":"R4","pred":"CauseOf","subj":"T5","obj":"T6"},{"id":"R5","pred":"ThemeOf","subj":"T7","obj":"T6"},{"id":"R6","pred":"ThemeOf","subj":"T9","obj":"T8"},{"id":"R7","pred":"CauseOf","subj":"T8","obj":"T10"}],"text":"Multifocal atrial and ventricular premature contractions with an increased risk of dilated cardiomyopathy caused by a Nav1.5 gain-of-function mutation (G213D).\nBACKGROUND: SCN5A mutations can lead to different cardiac diseases. Recently, SCN5A mutations have been linked to the clinical entity multifocal ectopic Purkinje-related premature contractions (MEPPC) characterized by ventricular ectopy and dilated cardiomyopathy.\nMETHODS \u0026 RESULTS: A family with a uniform MEPPC-like phenotype, associated with complex atrial and ventricular arrhythmias and dilated cardiomyopathy caused by a high frequency of ventricular ectopy was clinically assessed. Screening of the SCN5A gene revealed a missense mutation in the linker between segments 3 and 4 in domain 1 of the Nav1.5 protein, resulting in a glycine to aspartate substitution at position 213 (G213D). The phenotype co-segregated with the missense mutation. Electrophysiological studies of wild type (WT) hNav1.5 and hNav1.5_G213D expressed in CHO-K cells showed that the voltage of half-maximal activation (V½) was significantly more negative for hNav1.5_G213D compared to WT (V½=-38.7±0.5mV for WT and V½=-42.4±0.5mV for G213D; P\u003c0.001). This suggests activation of Nav1.5_G231D at more negative potentials. The V½ of steady-state inactivation was significantly shifted towards more positive values for Nav1.5_G213D (V½=-86.7±0.2mV for WT and -82.2±0.3mV for G213D; P\u003c0.001), also contributing to a gain-of-function phenotype. Flecainide and amiodarone markedly reduced premature atrial and ventricular contractions in four patients.\nCONCLUSION: The Nav1.5_G213D mutation is associated with a gain-of-function phenotype, multifocal atrial and ventricular ectopy and dilated cardiomyopathy. Since patients with a MEPPC-like phenotype may specifically benefit from Class-1 antiarrhythmic drugs or amiodarone, clinical identification of this disease entity is important."}

{"project":"name_no","denotations":[{"id":"T1","span":{"begin":83,"end":105},"obj":"Disease"},{"id":"T2","span":{"begin":118,"end":124},"obj":"Gene"},{"id":"T3","span":{"begin":125,"end":141},"obj":"PosReg"},{"id":"T19","span":{"begin":152,"end":157},"obj":"Var"},{"id":"T5","span":{"begin":178,"end":187},"obj":"Var"},{"id":"T6","span":{"begin":192,"end":199},"obj":"Reg"},{"id":"T7","span":{"begin":210,"end":226},"obj":"Disease"},{"id":"T9","span":{"begin":667,"end":672},"obj":"Gene"},{"id":"T8","span":{"begin":689,"end":706},"obj":"Var"},{"id":"T10","span":{"begin":781,"end":793},"obj":"Reg"},{"id":"T20","span":{"begin":847,"end":852},"obj":"Var"},{"id":"T12","span":{"begin":1605,"end":1611},"obj":"Gene"},{"id":"T21","span":{"begin":1612,"end":1617},"obj":"Var"},{"id":"T15","span":{"begin":1648,"end":1664},"obj":"PosReg"},{"id":"T18","span":{"begin":1721,"end":1743},"obj":"Disease"}],"relations":[{"id":"R15","pred":"ThemeOf","subj":"T2","obj":"T19"},{"id":"R16","pred":"CauseOf","subj":"T19","obj":"T3"},{"id":"R17","pred":"ThemeOf","subj":"T20","obj":"T10"},{"id":"R18","pred":"ThemeOf","subj":"T12","obj":"T21"},{"id":"R19","pred":"CauseOf","subj":"T21","obj":"T15"},{"id":"R20","pred":"ThemeOf","subj":"T18","obj":"T15"},{"id":"R3","pred":"ThemeOf","subj":"T1","obj":"T3"},{"id":"R4","pred":"CauseOf","subj":"T5","obj":"T6"},{"id":"R5","pred":"ThemeOf","subj":"T7","obj":"T6"},{"id":"R6","pred":"ThemeOf","subj":"T9","obj":"T8"},{"id":"R7","pred":"CauseOf","subj":"T8","obj":"T10"}],"text":"Multifocal atrial and ventricular premature contractions with an increased risk of dilated cardiomyopathy caused by a Nav1.5 gain-of-function mutation (G213D).\nBACKGROUND: SCN5A mutations can lead to different cardiac diseases. Recently, SCN5A mutations have been linked to the clinical entity multifocal ectopic Purkinje-related premature contractions (MEPPC) characterized by ventricular ectopy and dilated cardiomyopathy.\nMETHODS \u0026 RESULTS: A family with a uniform MEPPC-like phenotype, associated with complex atrial and ventricular arrhythmias and dilated cardiomyopathy caused by a high frequency of ventricular ectopy was clinically assessed. Screening of the SCN5A gene revealed a missense mutation in the linker between segments 3 and 4 in domain 1 of the Nav1.5 protein, resulting in a glycine to aspartate substitution at position 213 (G213D). The phenotype co-segregated with the missense mutation. Electrophysiological studies of wild type (WT) hNav1.5 and hNav1.5_G213D expressed in CHO-K cells showed that the voltage of half-maximal activation (V½) was significantly more negative for hNav1.5_G213D compared to WT (V½=-38.7±0.5mV for WT and V½=-42.4±0.5mV for G213D; P\u003c0.001). This suggests activation of Nav1.5_G231D at more negative potentials. The V½ of steady-state inactivation was significantly shifted towards more positive values for Nav1.5_G213D (V½=-86.7±0.2mV for WT and -82.2±0.3mV for G213D; P\u003c0.001), also contributing to a gain-of-function phenotype. Flecainide and amiodarone markedly reduced premature atrial and ventricular contractions in four patients.\nCONCLUSION: The Nav1.5_G213D mutation is associated with a gain-of-function phenotype, multifocal atrial and ventricular ectopy and dilated cardiomyopathy. Since patients with a MEPPC-like phenotype may specifically benefit from Class-1 antiarrhythmic drugs or amiodarone, clinical identification of this disease entity is important."}