Background:
Mutations in the Na
V
1.5 sodium channel macromolecular complex have been identified in some cases classified as idiopathic ventricular fibrillation (IVF). IVF and Brugada syndrome (BrS) are partially overlapping syndromes. Here, we report a mutation in
SCN3B-
encoded sodium channel β3 subunit as a novel pathogenic mechanism for IVF.
Methods:
Comprehensive open reading frame mutational analysis of
SCN5A, GPD1L,
and the beta subunit genes (
SCN1–4B
) was performed using PCR, DHPLC, and direct DNA sequencing of DNA extracted from a 20-year-old patient diagnosed with IVF. The
SCN3B
mutation was made by site directed mutagenesis and co-transfected with SCN5A into HEK-293 cells for functional chraracterization using the patch clamp technique.
Results:
A novel missense mutation, V54G-SCN3B, was identified in a 20-year-old male following collapse and external defibrillation from VF. After recovery, there was no detectable electrocardiographic abnormality. Imaging studies demonstrated a structurally normal heart, and the patient was diagnosed with IVF. The mutation was absent in 800 reference alleles and involved a highly conserved residue in the extracellular domain of the beta 3 subunit. No other mutations were identified in the 5 other genes. HEK cells expressing SCN5A and either WT-, or V54G-SCN3B were studied 24 hours after transfection. Cells expressing V54G-SCN3B showed significant decrease in sodium current density of 60±20 pA/pF compared to 203±35 pA/pF in WT-SCN3B (n=14–19). In addition V54G-SCN3B significantly shifted the activation curve +5 mV without affecting inactivation.
Conclusions:
This study provides the first molecular and cellular evidence implicating
SCN3B
in IVF. Given the marked loss-of-function to the sodium channel by V54G-SCN3B and the overlap between IVF and BrS, it will be interesting to determine whether mutations in
SCN3B
explain some cases of genotype negative Brugada syndrome.
The Brugada Syndrome Susceptibility Gene
HEY2
Modulates Cardiac Transmural Ion Channel Patterning and Electrical Heterogeneity
