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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.*

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

Circ.-Arrhythmia Electrophysiol. 5, 1098-1107 (2012)
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Background-Mutations in genes including SCN5A encoding the a-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. (Circ Arrhythm Electrophysiol. 2012;5:1098-1107.)
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Arrhythmia Mechanisms ; Genes ; Ion Channels ; Sarcoplasmic Reticulum; Sudden Cardiac Death ; Polymorphic Ventricular-tachycardia ; Ryanodine Receptor Gene ; St-segment-elevation ; Long Qt Syndrome ; J-wave Syndromes ; Missense Mutation ; Channel ; Prevalence ; Cardiomyopathy
ISSN (print) / ISBN 1941-3149
e-ISSN 1941-3084
Journal Circulation: Arrhythmia and Electrophysiology
Quellenangaben Volume: 5, Issue: 6, Pages: 1098-1107 Article Number: , Supplement: ,
Publisher Lippincott Williams & Wilkins
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)