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Introduction and Purpose: Variants in the cardiac ionic channel genes, including the SCN5A gene encoding Nav1.5 protein forming the pore-forming subunit of the sodium channel, can be identified in patients suffering from idiopathic ventricular fibrillation (iVF). This study investigates the clinical, genetic, and functional characteristics of a variant M135V-Nav1.5 associated with iVF. Methods: Detailed clinical and genetic testing was followed by electrophysiological analysis using the whole-cell patch clamp technique at 23°C on Chinese hamster ovary (CHO) cells transiently expressing the human Nav1.5 channels, either wild type (WT) or carrying the M135V-Nav1.5 variant (M135V), together with the wild type ß1-subunit. Results: The proband is a female diagnosed with iVF at the age of 40 after an episode of VF. ECG at rest and during and after the exercise test did not reveal any specific pathology, only rare ventricular extrasystoles were observed. No pathology was also apparent during echocardiography and Holter monitoring, thus, a diagnosis of iVF was made and the defibrillator was implanted as a secondary prevention of VF. An episode of non-sustained ventricular tachycardia was detected in the proband by the defibrillator last year. A heterozygous variant of uncertain significance (VUS) in the SCN5A gene, namely M135V-Nav1.5, was detected in the proband as well as in her asymptomatic father. Samples of peripheral blood were collected and human induced pluripotent stem cells (hiPSCs) of the proband (M135V), her asymptomatic father (M135V), and her healthy brother (WT) are currently being prepared. In the meantime, we have started the functional analysis of WT and M135V channels expressed in CHO cells. The electrophysiological characteristics of WT channels resemble those reported in previous studies (e.g. the half-maximal activation/inactivation voltage V1/2 of -29.4/-73.4 mV, the slope factors k of 6.87/-5.74; the fast and slow time constants of recovery from inactivation ?rec,f and ?rec,s of 5.2 and 195.4 ms at the holding potential of -120 mV, n = 8, and 78.9 and 875.7 ms at the holding potential of -80 mV, n = 9). Only limited data are currently available in M135V channels, thus, we have to wait to make any conclusions about their possible dysfunction. Conclusions: A female proband suffering from iVF and carrying a VUS SCN5A variant, M135V-Nav1.5, was identified and studied including detailed clinical and genetic investigation. Functional analysis of WT and M135V channels expressed in CHO cells has been started and hiPSCs of the proband, her asymptomatic father carrying the same variant, and her healthy brother are being prepared for the following cardiac differentiation and functional analysis in patient-specific hiPSC-derived cardiomyocytes.
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