title: Gating properties of SCN5A mutations and the response to mexiletine in long-QT syndrome type 3 patients.
abstract: 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.
  
  
  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.
authors: Molecular Cardiology, Fondazione Salvatore Maugeri, Via Maugeri 10/10A, 27100 Pavia, Italy.
authors: Yanfei
authors: Y
authors: Ruan
authors: Nian
authors: N
authors: Liu
authors: Raffaella
authors: R
authors: Bloise
authors: Carlo
authors: C
authors: Napolitano
authors: Silvia G
authors: SG
authors: Priori
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D015316:Genetic Therapy / Q000639:trends; D006801:Humans; D007223:Infant; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D008133:Long QT Syndrome / Q000145:classification / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008801:Mexiletine / Q000494:pharmacology / Q000627:therapeutic use*; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D008801:Mexiletine