Expression defects of the common polymorphisms S524Y and H558R in the Q1077 SCN5A variant can be rescued by mexiletine

Abstract

The cardiac Na channel encoded by SCN5A underlies excitability in the heart. “Loss of function” has been implicated in heritable arrhythmia syndromes such as Brugada syndrome, progressive cardiac conduction disease, and congenital sick sinus syndrome. The polymorphism H558R is very common with minor allelic frequency of 9.2% to 29% in different ethnic groups, and S524Y is common in the black population with a minor allelic frequency of 3.3%. Two splice variants of human SCN5A, one lacking a glutamine at position 1077 (Q1077del) and one containing Q1077, exist in every human in a 2:1 mRNA transcript ratio.