Phenotypic Severity of SCN5A -Related Bradycardia Is Independent of Dominant-Negative and Coupled Gating Effects

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BACKGROUND: Pathogenic SCN5A variants are associated with inherited arrhythmias such as long-QT syndrome, Brugada syndrome, and sick sinus syndrome. While Na v 1.5, an α-subunit of the cardiac sodium channel encoded by SCN5A , has been considered to function as a monomer, recent studies reveal that a reduction of sodium current in wild-type Na v 1.5 can be caused by dimerization with loss-of-function mutated Na v 1.5 through dominant-negative effects. However, the clinical significance of the dominant-negative effect remains unclear. METHOD: We genetically screened a family who presented with sick sinus syndrome and sudden cardiac death. Whole-cell patch-clamp study using HEK293 (human embryonic kidney) cells coexpressing wild-type and variant SCN5A was performed. Channel dimerization was assessed by coimmunoprecipitation and proximity ligation assays. Also, the effects of difopein, a high-affinity inhibitor of Na v 1.5 interaction via 14-3-3 proteins, were evaluated. RESULTS: The proband carried compound heterozygous variants p.T1396P and p.G833R. The whole-cell mode patch-clamp techniques demonstrated that the p.T1396P showed a dominant-negative effect on the peak sodium currents (37% decrease in I Na ) and altered gating properties (5.6-mV shift in steady-state inactivation) when expressed with wild-type SCN5A . These effects were abolished by difopein. p.G833R showed no dominant-negative or coupled gating effect but still formed dimers. The proband developed earlier and more severe bradycardia than the mother, who only carries p.T1396P, suggesting that loss of coupled gating effect contributed to the severe phenotype. CONCLUSIONS: Our findings suggest that coupled gating may be physiologically important for normal Na v 1.5 function, and its loss can exacerbate disease severity.

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