title: A trafficking defective, Brugada syndrome-causing SCN5A mutation rescued by drugs.
abstract: BACKGROUND
  The human cardiac SCN5A gene encodes for the alpha subunit of the human cardiac voltage-dependent sodium channel hNav1.5 [Neuron 28 (2) (2000) 365] and carries inward Na current (INa). Mutations in SCN5A cause arrhythmia syndromes including Brugada syndrome (BrS) and congenital long QT syndrome subtype 3 (LQT3). Here, we report a trafficking defective BrS-causing SCN5A mutation that was drug-rescued.
  
  
  RESULTS
  A 14-year-old Caucasian male was diagnosed with BrS with typical ECG pattern for BrS and ventricular fibrillation was easily induced. He also had significant HV interval delay ( approximately 65 ms) and high (31 J) defibrillation thresholds (DFTs). Genomic analysis revealed the SCN5A mutation (G1743R). We engineered G1743R into the cardiac Na channel and transfected HEK-293 cells for functional studies. The mutant channel yielded nearly undetectable sodium channel currents. Coexpression with the beta1 subunit, or incubation at low temperature did not increase current density. However, mexiletine, a sodium channel blocker, increased current density 93-fold in G1743R, but only twofold in WT.
  
  
  CONCLUSIONS
  This study identifies an expression-defective BrS mutation in SCN5A with pharmacological rescue. The profoundly decreased sodium current associated with the G1743R suggests a molecular basis for the delayed His-Purkinje conduction and elevated DFTs observed in the proband. Whether the mutant channel may be rescued in vivo by mexiletine and normalize the patient's electrophysiologic parameters remains to be tested.
authors.affiliation: Department of Medicine and Physiology, University of Wisconsin, Madison, WI, USA.
authors.forename: Carmen R
authors.initials: CR
authors.lastname: Valdivia
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Rok
authors.forename: Co-Burn J
authors.initials: CB
authors.lastname: Porter
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Munger
authors.forename: Arshad
authors.initials: A
authors.lastname: Jahangir
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Makielski
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
mesh_terms: D000293:Adolescent; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism; D008297:Male; D008801:Mexiletine / Q000494:pharmacology; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D010375:Pedigree; D011802:Quinidine / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D008801:Mexiletine; D011802:Quinidine