A novel disease gene for Brugada syndrome: Sarcolemmal membrane-associated protein gene mutations impair intracellular trafficking of hNav1.5

Taisuke Ishikawa, Akinori Sato, Cherisse A. Marcou, David J. Tester, Michael John Ackerman, Lia Crotti, Peter J. Schwartz, Young Keun On, Jeong Euy Park, Kazufumi Nakamura, Masayasu Hiraoka, Kiyoshi Nakazawa, Harumizu Sakurada, Takuro Arimura, Naomasa Makita, Akinori Kimura

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Abstract

Background: Mutations in genes including SCN5A encoding the α-subunit of the cardiac sodium channel (hNav1.5) cause Brugada syndrome via altered function of cardiac ion channels, but more than two-thirds of Brugada syndrome remains pathogenetically elusive. T-tubules and sarcoplasmic reticulum are essential in excitation of cardiomyocytes, and sarcolemmal membrane-associated protein (SLMAP) is a protein of unknown function localizing at T-tubules and sarcoplasmic reticulum. Methods and Results: We analyzed 190 unrelated Brugada syndrome patients for mutations in SLMAP. Two missense mutations, Val269Ile and Glu710Ala, were found in heterozygous state in 2 patients but were not found in healthy individuals. Membrane surface expression of hNav1.5 in the transfected cells was affected by the mutations, and silencing of mutant SLMAP by small interfering RNA rescued the surface expression of hNav1.5. Whole-cell patch-clamp recordings of hNav1.5-expressing cells transfected with mutant SLMAP confirmed the reduced hNav1.5 current. Conclusions: The mutations in SLMAP may cause Brugada syndrome via modulating the intracellular trafficking of hNav1.5 channel.

Original languageEnglish (US)
Pages (from-to)1098-1107
Number of pages10
JournalCirculation: Arrhythmia and Electrophysiology
Volume5
Issue number6
DOIs
StatePublished - Dec 2012

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Keywords

  • Arrhythmia mechanisms
  • Genes
  • Ion channels
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Ishikawa, T., Sato, A., Marcou, C. A., Tester, D. J., Ackerman, M. J., Crotti, L., Schwartz, P. J., On, Y. K., Park, J. E., Nakamura, K., Hiraoka, M., Nakazawa, K., Sakurada, H., Arimura, T., Makita, N., & Kimura, A. (2012). A novel disease gene for Brugada syndrome: Sarcolemmal membrane-associated protein gene mutations impair intracellular trafficking of hNav1.5. Circulation: Arrhythmia and Electrophysiology, 5(6), 1098-1107. https://doi.org/10.1161/CIRCEP.111.969972