A novel SCN3B in-frame codon deletion in a Brugada syndrome patient: Implications for disrupted NaV1.5 function

J Mol Cell Cardiol. 2025 Jan 4:S0022-2828(24)00226-8. doi: 10.1016/j.yjmcc.2024.12.011. Online ahead of print.

Abstract

Introduction: Brugada Syndrome (BrS) is an inherited arrhythmia syndrome characterised by ST-segment elevation in the right precordial ECG leads and is associated with an increased risk of sudden cardiac death. We identify and characterise a novel SCN3B variant encoding the regulatory β3-subunit of the cardiac voltage-gated sodium channel, NaV1.5.

Methods and results: A 54-year-old Caucasian male presented with palpitations and dizziness. An ECG identified a spontaneous type 1 BrS pattern and review of his medical records revealed a prior type 1 BrS ECG. Next generation sequencing of a BrS risk panel of genes identified a novel SCN3B deletion (c. c412-414, p.T138Del) yielding a single amino acid deletion. No other pathogenic variants were identified. Using site-directed mutagenesis we made the β3-ΔT138 variant and examined structural and functional effects in a heterologous system. Computational predictions together with circular dichroism spectroscopy showed highly localised structural perturbations with minimal effect on the gross protein architecture. Biotinylation, co-immunoprecipitation and surface cross-linking experiments identified normal β3 surface expression and interaction with NaV1.5. Electrophysiological analysis identified reduced peak current and channel availability. Additionally, an accelerated fast inactivation was observed only in the presence of both wild-type and ΔT138 β3-subunits, reflecting the heterozygous individual. These effects are consistent with a loss-of-function phenotype.

Conclusion: A novel BrS associated SCN3B deletion introduced minimally disruptive structural perturbations to the regulatory β3-subunit of NaV1.5, yet exerted significant electrophysiological effects. This variant highlights nuances of the NaV1.5-β3 interaction and its role in maintaining normal cardiac excitability.

Keywords: Brugada syndrome; Fast inactivation; Nav1.5; Patch clamp; SCN3B; SCN5A.