Journal of molecular and cellular cardiology
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J. Mol. Cell. Cardiol. · May 2019
Case Reports Clinical TrialEnhanced closed-state inactivation of mutant cardiac sodium channels (SCN5A N1541D and R1632C) through different mechanisms.
SCN5A variants can be associated with overlapping phenotypes such as Brugada syndrome (BrS), sinus node dysfunction and supraventricular tachyarrhythmias. Our genetic screening of SCN5A in 65 consecutive BrS probands revealed two patients with overlapping phenotypes: one carried an SCN5A R1632C (in domain IV-segment 4), which we have previously reported, the other carried a novel SCN5A N1541D (in domain IV-segment 1). ⋯ Both N1541D-INa and R1632C-INa exhibited marked enhancement of CSI, but through different mechanisms. The data provided a novel understanding of the mechanisms of CSI of INa. Clinically, the enhanced CSI of N1541D-INa leads to a severe loss-of-function of INa at voltages near the physiological resting membrane potential (~-90 mV) of cardiac myocytes; this can be attributable to the patient's phenotypic manifestations.