Idiopathic ventricular fibrillation: a role of variants in the hERG gene

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14110%2F24%3A00136409" target="_blank" >RIV/00216224:14110/24:00136409 - isvavai.cz</a>

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Idiopathic ventricular fibrillation: a role of variants in the hERG gene

Popis výsledku v původním jazyce

Introduction: Variants in the cardiac ionic channel genes, including the hERG gene encoding -subunit of rapid delayed rectifier, can be identified in patients suffering from idiopathic ventricular fibrillation (iVF). A complex analysis is needed to consider the pathogenic character of an identified variant. Purpose: This study revealed 1 (out of 25) probands suffering from iVF and carrying even two hERG variants. Clinical and genetic characteristics of the proband and channel dysfunction are being examined. Methods: Clinical and genetic investigation was followed by electrophysiological experiments using whole-cell patch clamp technique at 37°C on Chinese hamster ovary cells transiently expressing human hERG channels, wild type (WT) and carrying S1021Qfs*98 variant. Results: The first VF episode occurred in the female proband at the age of 22. QTc interval (Fridericia) was 460 ms at rest and 420 ms during recovery after exercise. No pathology has been revealed (exercise test, Holter monitoring, echocardiography). Hence, the diagnosis of iVF was considered, defibrillator was implanted, and treatment using betaxolol wa started. Repeated episodes of VF were reported during the following years (16/7 years). Two hERG variants in trans, likely benign p.A228V and likely pathogenic p.S1021Qfs*98, were identified in the proband. The biophysical analysis performed in S1021Qfs*98 channels has not revealed any alteration in voltage- and time-dependent characteristics of the activation, deactivation, and inactivation, but the tail current was significantly decreased (by 70 % at 0 mV). Conclusions: A proband carrying two hERG variants but showing physiological QTc, thus, being diagnosed as iVF was identified and studied. Functional analysis of S1021Qfs*98 channels revealed a significantly decreased tail current with unaltered gating. The functional analysis of A228V and A228V/S1021Qfs*98 channels and analysis of channel expression/trafficking will follow.

Název v anglickém jazyce

Idiopathic ventricular fibrillation: a role of variants in the hERG gene

Popis výsledku anglicky

Introduction: Variants in the cardiac ionic channel genes, including the hERG gene encoding -subunit of rapid delayed rectifier, can be identified in patients suffering from idiopathic ventricular fibrillation (iVF). A complex analysis is needed to consider the pathogenic character of an identified variant. Purpose: This study revealed 1 (out of 25) probands suffering from iVF and carrying even two hERG variants. Clinical and genetic characteristics of the proband and channel dysfunction are being examined. Methods: Clinical and genetic investigation was followed by electrophysiological experiments using whole-cell patch clamp technique at 37°C on Chinese hamster ovary cells transiently expressing human hERG channels, wild type (WT) and carrying S1021Qfs*98 variant. Results: The first VF episode occurred in the female proband at the age of 22. QTc interval (Fridericia) was 460 ms at rest and 420 ms during recovery after exercise. No pathology has been revealed (exercise test, Holter monitoring, echocardiography). Hence, the diagnosis of iVF was considered, defibrillator was implanted, and treatment using betaxolol wa started. Repeated episodes of VF were reported during the following years (16/7 years). Two hERG variants in trans, likely benign p.A228V and likely pathogenic p.S1021Qfs*98, were identified in the proband. The biophysical analysis performed in S1021Qfs*98 channels has not revealed any alteration in voltage- and time-dependent characteristics of the activation, deactivation, and inactivation, but the tail current was significantly decreased (by 70 % at 0 mV). Conclusions: A proband carrying two hERG variants but showing physiological QTc, thus, being diagnosed as iVF was identified and studied. Functional analysis of S1021Qfs*98 channels revealed a significantly decreased tail current with unaltered gating. The functional analysis of A228V and A228V/S1021Qfs*98 channels and analysis of channel expression/trafficking will follow.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30201 - Cardiac and Cardiovascular systems

Projekt

<a href="/cs/project/NU22-02-00348" target="_blank" >NU22-02-00348: Funkční hodnocení genetických variant u případů klinicky „skutečné“ idiopatické fibrilace komor: in vitro a in silico modelování s cílem odhalit arytmogenní mechanismus</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů