Published Online
on August 13, 2007

A more recent version of this article appeared on September 4, 2007

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Submitted on April 6, 2007
Accepted on May 30, 2007

Gating Properties of SCN5A Mutations and the Response to Mexiletine in Long-QT Syndrome Type 3 Patients

Yanfei Ruan MD, Nian Liu MD, Raffaella Bloise MD, Carlo Napolitano MD, PhD, and Silvia G. Priori MD, PhD^*

From the Molecular Cardiology, Fondazione Salvatore Maugeri (Y.R., N.L., R.B., C.N., S.G.P.), and Department of Cardiology, University of Pavia (S.G.P.), Pavia, Italy.

^* To whom correspondence should be addressed. E-mail: spriori{at}fsm.it.

Background—Mexiletine (Mex) has been proposed as a gene-specific therapy for patients with long-QT syndrome type 3 (LQT3) caused by mutations in the cardiac sodium channel gene (SCN5A). The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations. We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations.

Methods and Results—We identified 4 SCN5A mutations in 5 symptomatic LQT3 patients with different responses to Mex (6 to 8 mg · kg^-1 · d^-1). We classified the mutations as sensitive to Mex (P1332L, R1626P; 10% of QTc shortening and QTc <500 ms or no arrhythmias) or insensitive to Mex (S941N, M1652R; negligible or no QTc shortening and sudden death). We measured Na⁺ current from HEK 293 cells transfected with wild-type (WT) or mutant Nav1.5. All mutations showed impaired inactivation of Na⁺ current, but the mutations identified in patient responders to Mex (P1332L, R1626P) showed a hyperpolarizing shift of V_1/2 of steady-state inactivation. Furthermore, Mex produced use-dependent block with the order R1626P=P1332L>S941N=WT>M1652R, suggesting that Mex-sensitive mutants present prolonged recovery from Mex block.

Conclusions—We propose that voltage dependence of channel availability and shifts of V_1/2 of steady-state inactivation correlate with the clinical response observed in LQT3 patients. This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3.

Key words: electrophysiology • genetics • long-QT syndrome • pharmacology • sodium • ion channels

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