SCN1Bβ mutations that affect their association with Kv4.3 underlie early repolarization syndrome.

Background: Abnormal cardiac ion channels current, including transient outward potassium current (I ), is associated with early repolarization syndrome (ERS). Previous studies showed that mutations in SCN1Bβ both to increase the I current and to decrease the sodium current. Yet its role in ERS remains unknown.

Objective: To determine the role of mutations in the SCN1Bβ subunits in ERS.

Methods: We screened for mutations in the SCN1B genes from four families with ERS. Wild-type and mutant SCN1Bβ genes were co-expressed with wild-type KCND3 in human embryonic kidney cells (HEK293). Whole-cell patch-clamp technique and co-immunoprecipitation were used to study the electrophysiological properties and explore the underlying mechanisms.

Results: S248R and R250T mutations in SCN1Bβ were detected in 4 families' probands. Neither S248R nor R250T mutation had significant influence on the sodium channel current density (I ) when co-expressed with SCN5A/WT. Co-expression of KCND3/WT and SCN1Bβ/S248R or SCN1Bβ/R250T increased the transient outward potassium current I by 27.44% and 199.89%, respectively (P < 0.05 and P < 0.01, respectively) when compared with SCN1Bβ/WT. Electrophysiological properties showed that S248R and R250T mutations decreased the steady-state inactivation and recovery from inactivation of I channel. Co-immunoprecipitation study demonstrated an increased association between SCN1Bβ mutations and Kv4.3 compared with SCN1Bβ/WT (P < 0.05 and P < 0.01, respectively).

Conclusion: The S248R and R250T mutations of SCN1Bβ gene caused gain-of-function of I by associated with Kv4.3, which maybe underlie the ERS phenotype of the probands.