Abstract 2713: MOG1 Mutations Associated With Brugada Syndrome Electrocardiogram Pattern
Purpose: Brugada syndrome (BrS) is a genetic disorder associated with arrhythmias and sudden cardiac death (SCD), caused mainly by mutations in the SCN5A gene, encoding the α subunit of the cardiac sodium channel, Nav1.5. Most mutations lead to a loss of function, characterized by reduced sodium current density. However, less than 30% of probands have SCN5A mutations, suggesting that other genes are implicated. MOG1 has recently been identified as a new co-factor of Nav1.5, potentially regulating sodium channel expression and trafficking. Therefore, we hypothesized that mutations in MOG1 may be related to BrS.
Methods: MOG1 was screened by direct sequencing in 190 BrS patients who were negative for SCN5A mutations. Functional effects were investigated by using whole-cell patch-clamp techniques in stably expressing Nav1.5 HEK293 cells, transiently transfected with wild-type (WT) or mutant MOG1 or empty vector (control cells, CT).
Results: Genetic screening revealed two mutations, c.181G > T (p. E61X) and c.249G > C (p. E83D). The nonsense mutation was found in an asymptomatic male patient with a type-1 BrS ECG pattern, parietal block, and sustained polymorphic ventricular tachyarrhythmia with programmed stimulation. The missense mutation was carried by a symptomatic female patient who also had a type-1 BrS ECG pattern and a resuscitated SCD after overdose. She died 4 days later without further investigations. In cells, overexpression of WT MOG1 significantly increased sodium current density compared to CT cells (INa : CT −91.2+/− 17.3 pA/pF n = 14; MOG1 WT −185.3 +/− 42.0 pA/pF n = 12; p* = 0.039), while this effect was not observed with the p. E83D mutant (INa: MOG1 E83D −89.5 +/−28.4 pA/pF n = 12). No differences in biophysical properties of the sodium channel (activation/inactivation) were detected.
Conclusion: We provide for the first time clinical and molecular evidence implicating MOG1 in patients displaying BrS ECG patterns. Electrophysiological studies on p. E83D MOG1 mutant protein demonstrated a loss of function in sodium current density suggesting that mutant protein may alter normal expression and/or trafficking of Nav1.5. Our findings support MOG1 as a new suceptibility gene for life-threatening ventricular arrhythmias.