Effects of mexiletine on a race-specific mutation in Nav1.5 associated with long QT syndrome.

Abstract

Mutations in cardiac Nav1.5 have been associated with LQT syndrome, Brugada syndrome, and sudden arrhythmia death syndrome. Genetic studies showed that Nav1.5 mutations vary across race-ethnic groups. The Nav1.5 mutation P1090L was linked with familial long QT syndrome (LQTS) and was identified as an ethnic-specific variant in Asians. To explore the role of the P1090L in the LQT syndrome, we characterized the effects of the mutation on the Nav1.5 channel function. We found that the P1090L mutation altered the gating process of the channel and exhibited an enhanced window current. Treatment with mexiletine reversed the depolarization shift of the steady-state inactivation produced by the mutation. Mexiletine modified the recovery and development of inactivation of the mutation and reduced the mutated channel's availability. We characterized that the P1090L is a gain-of-function, the mutation presented a larger window current and increased channel availability. Treatment with mexiletine rescued the dysfunctional inactivation of the mutation. The results might potentially enable a mechanism-based approach to the treatment of LQTS.