Key result
The novel T1857I mutation in SCN5A causes a net gain-of-function in Nav1.5 gating, leading to increased window currents and ventricular afterdepolarizations that predispose carriers to tachy-arrhythmias.
Why the study?
To functionally characterize a novel Nav1.5 variant (T1857I) linked to a CPVT-like phenotype with atrial and ventricular arrhythmias and sudden cardiac death, and determine links between channel gating and clinical phenotype.
The novel T1857I mutation in SCN5A causes a net gain-of-function in Nav1.5 gating, leading to increased window currents and ventricular afterdepolarizations, which provides a mechanistic explanation for the atypical CPVT-like arrhythmic phenotype observed in carriers.
May inform variant-specific arrhythmia risk assessment; leaves open human validation and therapeutic targeting.
Background Sudden cardiac death (SCD) is an unexpected death that occurs within an hour of the onset of symptoms. Hereditary primary electrical disorders account for up to 1/3 of all SCD cases in younger individuals and include conditions such as catecholaminergic polymorphic ventricular tachycardia (CPVT). These disorders are caused by mutations in the genes encoding cardiac ion channels, hence they are known as cardiac channelopathies. We identified a novel variant, T1857I, in the C-terminus of Nav1.5 ( SCN5A ) linked to a family with a CPVT-like phenotype characterized by atrial tachy-arrhythmias and polymorphic ventricular ectopy occurring at rest and with adrenergic stimulation, and a strong family history of SCD. Objective Our goal was to functionally characterize the novel Nav1.5 variant and determine a possible link between channel gating and clinical phenotype. Methods We first used electrocardiogram recordings to visualize the patient cardiac electrical properties. Then, we performed voltage-clamp of transiently transfected CHO cells. Lastly, we used the ventricular/atrial models to visualize gating defects on cardiac excitability. Results Voltage-dependences of both activation and inactivation were right-shifted, the overlap between activation and inactivation predicted increased window currents, the recovery from fast inactivation was slowed, there was no significant difference in late currents, and there was no difference in use-dependent inactivation. The O’Hara-Rudy model suggests ventricular afterdepolarizations and atrial Grandi-based model suggests a slight prolongation of atrial action potential duration. Conclusion We conclude that T1857I likely causes a net gain-of-function in Nav1.5 gating, which may in turn lead to ventricular afterdepolarization, predisposing carriers to tachy-arrhythmias.
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Ghovanloo et al. (2020) studied Catecholaminergic polymorphic ventricular tachycardia (CPVT)-like phenotype (n=2). T1857I mutation in SCN5A vs. Wild-type (WT) Nav1.5 was evaluated on Biophysical properties of Nav1.5 (voltage-dependence of activation and inactivation). The novel T1857I mutation in SCN5A causes a net gain-of-function in Nav1.5 gating, leading to increased window currents and ventricular afterdepolarizations that predispose carriers to tachy-arrhythmias.
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