Abstract 17305: Overexpression of Sodium Channel beta 4 Subunit is Responsible for Increase in Late Sodium Current in Mice with Mecp2 Deficiency

Abstract

Introduction: The methyl-CpG-binding protein (MeCP2) is an epigenetic modifier of genetic expression and repression, and its dysfunction has been shown to cause Rett Syndrome, a progressive neurological disorder associated with sudden cardiac death. MeCP2 dysfunction has also been shown to be associated with QT interval in human patients, however the underlying mechanisms are unclear. We evaluated mice deficient in MeCP2 (KO) to determine whether there were differences in expression of genes commonly associated with long QT syndrome (LQTS). Hypothesis: MeCP2 dysfunction alters expression of plasma membrane ion channels or its interacting proteins, which are necessary for normal cardiomyocyte action potential. Methods and Results: qPCR was performed on wild type mice (WT) and KO heart lysates. Among 11 LQTS genes, SCN4B, one of beta subunits of the cardiac voltage gated sodium channel, was elevated 2.5 fold (n = 3, P = 0.04), while other 10 LQTS genes were not significantly altered. Western blot analysis on heart lysates showed increase of SCN4B protein in KO, consistent with immunostaining on isolated ventricular myocytes, which showed a qualitative increase of plasma membrane enhancement of SCN4B. Sodium current was recorded from a holding potential of -120 mV and activated to -20 mV. There was no change in peak sodium current, however, late sodium current was significantly increased in KO compared to WT (WT, -170.4 ± 29.2 pA, n = 5 vs. Rett, -590.0 ± 145.7 pA, n = 5; WT vs. Rett, p < 0.01). and Phenytoin, a late sodium current blocking agent, reduced late sodium current near normal levels (Rett + Phenytoin, -183.8 ± 40.6 pA, n = 5; Rett vs. Rett + Phenytoin, p < 0.05). Conclusion: Mice deficient in MeCP 2 have an increase in SCN4B expression, which may be associated with prolongation of QT interval. Phenytoin inhibits the late sodium current and may be an effective treatment for prevention of arrhythmias in patients with MeCP2 dysfunction.