Abstract 926: Gating Properties of SCN5A Mutants Predict Response to Mexiletine in LQT3 Patients
Background: Although mexiletine (Mex) has been proposed as a gene specific therapy in LQT3 patients, the QT shortening effect varies among patients harboring different mutations. Since Mex block of sodium channel Nav1.5 depends upon gating state and LQT3 mutations also alter the channel gating, we hypothesize that the clinical effect of Mex in LQT3 could be predicted on the basis of the in vitro characterization of Nav1.5 gating defect induced by specific mutations.
Methods and Results: We identified four Nav1.5 mutations occurring in LQT3 patients displaying different amount of QTc shortening (QTcSH) during Mex treatment (6 – 8 mg/kg/day): “sensitive” (P1332L, R1626P; >40ms of QTcSH), “intermediate” (S941N; 20–30ms of QTcSH) and “insensitive” mutations (M1652R; <15ms of QTcSH). We measured whole-cell Na current from HEK 293 cells transfected with wild-type (WT) or mutant Nav1.5 (holding -100 mV). All four mutations showed impaired inactivation which was compatible with the phenotype of LQT. The order of V1/2 of steady state inactivation (SSI) curves is R1626P = P1332L < S941N = WT < M1652R (−69mV, −68mV, −62mV, −62mV, −55mV respectively). Mex produced a tonic block (TB) following the rank order: R1626P > P1332L > S941N = WT > M1652R that were much higher than the therapeutic concentration (>170μM). Mex produced use-dependent block (UDB) with an order R1626P = P1332L > S941N = WT > M1652R (IC50: 8.8μM, 8.8μM, 26.2μM, 27.8μM and 54.2μM respectively). R1626P and P1332L showed prolonged recovery from 10μM Mex block compared with S941N and WT, while M1652R showed faster recovery from 10μM Mex block.
Conclusions: Our data suggest that the effect of sodium channel blockers in LQT3 might be mutation-specific and that in vitro testing may help predict the clinical response to therapy with Mex in LQT3 patients. Indeed the analysis of voltage dependence of channel availability and shifts of V1/2 of SSI allow to rank mutations (more negative V1/2 correspond to better clinical effect) in term of IC50 of UDB, which, in turn parallels the clinical response in four mutations.