TMEM43 mutation p.S358L alters intercalated disc protein expression and reduces conduction velocity in arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a myocardial disease characterized by fibro-fatty replacement of myocardium in the right ventricular free wall and frequently results in life-threatening ventricular arrhythmias and sudden cardiac death. A heterozygous missense mutation in th...

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Bibliographic Details
Published in:	PloS one 2014-10, Vol.9 (10), p.e109128-e109128
Main Authors:	Siragam, Vinayakumar, Cui, Xuezhi, Masse, Stephane, Ackerley, Cameron, Aafaqi, Shabana, Strandberg, Linn, Tropak, Michael, Fridman, Michael D, Nanthakumar, Kumaraswamy, Liu, Jun, Sun, Yu, Su, Bin, Wang, Caroline, Liu, Xiaoru, Yan, Yuqing, Mendlowitz, Ariel, Hamilton, Robert M
Format:	Article
Language:	eng
Subjects:	Arrhythmogenic Right Ventricular Dysplasia - genetics Arrhythmogenic Right Ventricular Dysplasia - physiopathology Biology Biology and Life Sciences Cardiology Cardiomyocytes Cardiomyopathy Catenin Cell culture Cell junctions Communication Conduction Connexin 43 Cytoplasm Cytoskeleton Desmosomes - metabolism DISC protein Dyes Electron microscopy Endoplasmic Reticulum - genetics Gap Junctions - genetics Gene Expression Regulation Genes Genetic aspects Health care networks Heart Heart diseases Hospitals Humans Immunofluorescence Industrial engineering Kinases Laboratories Localization Medicine Medicine and Health Sciences Membrane Proteins - biosynthesis Membrane Proteins - genetics Missense mutation Mutation Mutation, Missense Myocardial diseases Myocardium Myocardium - metabolism Myocardium - pathology Pathogenesis Phosphorylation Physiology Proteins Transmission electron microscopy Velocity Ventricle Zonula occludens-1 protein α-Catenin
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Summary:	Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a myocardial disease characterized by fibro-fatty replacement of myocardium in the right ventricular free wall and frequently results in life-threatening ventricular arrhythmias and sudden cardiac death. A heterozygous missense mutation in the transmembrane protein 43 (TMEM43) gene, p.S358L, has been genetically identified to cause autosomal dominant ARVC type 5 in a founder population from the island of Newfoundland, Canada. Little is known about the function of the TMEM43 protein or how it leads to the pathogenesis of ARVC. We sought to determine the distribution of TMEM43 and the effect of the p.S358L mutation on the expression and distribution of various intercalated (IC) disc proteins as well as functional effects on IC disc gap junction dye transfer and conduction velocity in cell culture. Through Western blot analysis, transmission electron microscopy (TEM), immunofluorescence (IF), and electrophysiological analysis, our results showed that the stable expression of p.S358L mutation in the HL-1 cardiac cell line resulted in decreased Zonula Occludens (ZO-1) expression and the loss of ZO-1 localization to cell-cell junctions. Junctional Plakoglobin (JUP) and α-catenin proteins were redistributed to the cytoplasm with decreased localization to cell-cell junctions. Connexin-43 (Cx43) phosphorylation was altered, and there was reduced gap junction dye transfer and conduction velocity in mutant TMEM43-transfected cells. These observations suggest that expression of the p.S358L mutant of TMEM43 found in ARVC type 5 may affect localization of proteins involved in conduction, alter gap junction function and reduce conduction velocity in cardiac tissue.
ISSN:	1932-6203 1932-6203