A trafficking defective, Brugada syndrome-causing SCN5A mutation rescued by drugs

Carmen R. Valdivia, David J. Tester, Benjamin A. Rok, Co Burn J. Porter, Thomas M. Munger, Arshad Jahangir, Jonathan C. Makielski, Michael J. Ackerman

Research output: Contribution to journalArticle

105 Scopus citations

Abstract

Background: The human cardiac SCN5A gene encodes for the α 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.

Original languageEnglish (US)
Pages (from-to)53-62
Number of pages10
JournalCardiovascular research
Volume62
Issue number1
DOIs
StatePublished - Apr 1 2004

Keywords

  • Arrhythmia (mechanisms)
  • Brugada syndrome
  • Genetic testing
  • Ion channels
  • Na-channel
  • Na1.5
  • Official gene designation for the cardiac sodium channel gene residing on chromosome 3p21
  • SCN5A

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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  • Cite this

    Valdivia, C. R., Tester, D. J., Rok, B. A., Porter, C. B. J., Munger, T. M., Jahangir, A., Makielski, J. C., & Ackerman, M. J. (2004). A trafficking defective, Brugada syndrome-causing SCN5A mutation rescued by drugs. Cardiovascular research, 62(1), 53-62. https://doi.org/10.1016/j.cardiores.2004.01.022