© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
A trafficking defective, Brugada syndrome-causing SCN5A mutation rescued by drugs
aDepartment of Medicine and Physiology, University of Wisconsin, Madison, WI, USA
bDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester MN, USA
cDepartment of Pediatrics/Division of Pediatric Cardiology, Mayo Clinic College of Medicine, Rochester MN, USA
dDepartment of Medicine/Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester MN, USA
* Corresponding author. Sudden Death Genomics Laboratory, Mayo Clinic College of Medicine, Guggenheim 501, 200 First Street SW, Rochester, MN 55905, USA. Tel.: +1-507-284-0101; fax: +1-507-284-3757. Email address: ackerman.michael{at}mayo.edu
Background: The human cardiac SCN5A gene encodes for the 
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.
Methods and 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 (
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 β1 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.
KEYWORDS Arrhythmia (mechanisms); Na-channel; Ion channels; Brugada syndrome; SCN5A; NaV1.5; Genetic testing
Abbreviations: SCN5A, official gene designation for the cardiac sodium channel gene residing on chromosome 3p21 • NaV1.5, nomenclature for the channel protein product of SCN5A • hH1c, cDNA clone used to construct the mutant channel for heterologous expression • WT, "wild-type" Na channel • G1743R, mutated SCN5A channel containing an arginine (R) at position 1743 instead of the normal glycine (G) residue
1 Contributed equally to this work.
Time for primary review 10 days
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