Investigations of the Na_vβ1b sodium channel subunit in human ventricle; functional characterization of the H162P Brugada syndrome mutant

Abstract

Brugada syndrome (BrS) is a rare inherited disease that can give rise to ventricular arrhythmia and ultimately sudden cardiac death. Numerous loss-of-function mutations in the cardiac sodium channel Nav1.5 have been associated with BrS. However, few mutations in the auxiliary Navβ1-4 subunits have been linked to this disease. Here we investigated differences in expression and function between Navβ1 and Navβ1b and whether the H162P/Navβ1b mutation found in a BrS patient is likely to be the underlying cause of disease. The impact of Navβ subunits was investigated by patch-clamp electrophysiology, and the obtained in vitro values were used for subsequent in silico modeling. We found that Navβ1b transcripts were expressed at higher levels than Navβ1 transcripts in the human heart. Navβ1 and Navβ1b coexpressed with Nav1.5 induced a negative shift on steady state of activation and inactivation compared with Nav1.5 alone. Furthermore, Navβ1b was found to increase the current level when coexpressed with Nav1.5, Navβ1b/H162P mutated subunit peak current density was reduced by 48% (-645 ± 151 vs. -334 ± 71 pA/pF), V1/2 steady-state inactivation shifted by -6.7 mV (-70.3 ± 1.5 vs. -77.0 ± 2.8 mV), and time-dependent recovery from inactivation slowed by >50% compared with coexpression with Navβ1b wild type. Computer simulations revealed that these electrophysiological changes resulted in a reduction in both action potential amplitude and maximum upstroke velocity. The experimental data thereby indicate that Navβ1b/H162P results in reduced sodium channel activity functionally affecting the ventricular action potential. This result is an important replication to support the notion that BrS can be linked to the function of Navβ1b and is associated with loss-of-function of the cardiac sodium channel.

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

“…Some studied reported that SCN1Bβ variants reduced sodium currents by accelerating recovery from inactivation and decreasing the slow inactivation rate. 29,38 In contrast, the mutations we reported in the present study could not alter Nav1.5 channel currents significantly. We have noted a previously study identified the same mutations of SCN1Bβ in three asymptomatic members from a family with Brugada syndrome and sick sinus syndrome.…”

“…The effects of SCN1Bβ variants on Na v 1.5 currents had been described earlier. Some studied reported that SCN1Bβ variants reduced sodium currents by accelerating recovery from inactivation and decreasing the slow inactivation rate . In contrast, the mutations we reported in the present study could not alter Nav1.5 channel currents significantly.…”

Brugada Syndrome: Oligogenic or Mendelian Disease?

“…In another study, the IVS3+ 2996(TTA)8 allele was described as an SCN1B polymorphism that may make middle-aged, male Japanese more susceptible to BrS, while not causing BrS by itself [89]. Furthermore, a study by Yuan and colleagues [49] identified the H162P mutation in the SCN1Bb gene in a BrS patient, and, extrapolating that mutation to in vitro studies, found that this mutation reduces the action potential amplitude and conduction velocity, creating an increased risk of ventricular arrhythmia. However, genotype-phenotype correlations in families with BrS and reported pathogenic SCN1B or SCN1Bb variants are lacking [48].…”

Voltage-Gated Sodium Channel β Subunits and Their Related Diseases

“…Multiple mutations in SCN1B have also been linked to Brugada syndrome (BrS) (Holst et al 2012; Hu et al 2012; Watanabe et al 2008; Yuan et al 2014). BrS patients have an increased risk of sudden cardiac death due to VF (Watanabe et al 2008).…”