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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ftdoajarticles:oai:doaj.org/article:81dc701f89c5477fb1ceeb469e49c9d7 2023-05-15T17:22:41+02:00 TMEM43 mutation p.S358L alters intercalated disc protein expression and reduces conduction velocity in arrhythmogenic right ventricular cardiomyopathy. Vinayakumar Siragam Xuezhi Cui Stephane Masse Cameron Ackerley Shabana Aafaqi Linn Strandberg Michael Tropak Michael D Fridman Kumaraswamy Nanthakumar Jun Liu Yu Sun Bin Su Caroline Wang Xiaoru Liu Yuqing Yan Ariel Mendlowitz Robert M Hamilton 2014-01-01T00:00:00Z https://doi.org/10.1371/journal.pone.0109128 https://doaj.org/article/81dc701f89c5477fb1ceeb469e49c9d7 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC4208740?pdf=render https://doaj.org/toc/1932-6203 1932-6203 doi:10.1371/journal.pone.0109128 https://doaj.org/article/81dc701f89c5477fb1ceeb469e49c9d7 PLoS ONE, Vol 9, Iss 10, p e109128 (2014) Medicine R Science Q article 2014 ftdoajarticles https://doi.org/10.1371/journal.pone.0109128 2022-12-31T00:51:25Z 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. Article in Journal/Newspaper Newfoundland Directory of Open Access Journals: DOAJ Articles Canada PLoS ONE 9 10 e109128 |
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English |
topic |
Medicine R Science Q |
spellingShingle |
Medicine R Science Q Vinayakumar Siragam Xuezhi Cui Stephane Masse Cameron Ackerley Shabana Aafaqi Linn Strandberg Michael Tropak Michael D Fridman Kumaraswamy Nanthakumar Jun Liu Yu Sun Bin Su Caroline Wang Xiaoru Liu Yuqing Yan Ariel Mendlowitz Robert M Hamilton TMEM43 mutation p.S358L alters intercalated disc protein expression and reduces conduction velocity in arrhythmogenic right ventricular cardiomyopathy. |
topic_facet |
Medicine R Science Q |
description |
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. |
format |
Article in Journal/Newspaper |
author |
Vinayakumar Siragam Xuezhi Cui Stephane Masse Cameron Ackerley Shabana Aafaqi Linn Strandberg Michael Tropak Michael D Fridman Kumaraswamy Nanthakumar Jun Liu Yu Sun Bin Su Caroline Wang Xiaoru Liu Yuqing Yan Ariel Mendlowitz Robert M Hamilton |
author_facet |
Vinayakumar Siragam Xuezhi Cui Stephane Masse Cameron Ackerley Shabana Aafaqi Linn Strandberg Michael Tropak Michael D Fridman Kumaraswamy Nanthakumar Jun Liu Yu Sun Bin Su Caroline Wang Xiaoru Liu Yuqing Yan Ariel Mendlowitz Robert M Hamilton |
author_sort |
Vinayakumar Siragam |
title |
TMEM43 mutation p.S358L alters intercalated disc protein expression and reduces conduction velocity in arrhythmogenic right ventricular cardiomyopathy. |
title_short |
TMEM43 mutation p.S358L alters intercalated disc protein expression and reduces conduction velocity in arrhythmogenic right ventricular cardiomyopathy. |
title_full |
TMEM43 mutation p.S358L alters intercalated disc protein expression and reduces conduction velocity in arrhythmogenic right ventricular cardiomyopathy. |
title_fullStr |
TMEM43 mutation p.S358L alters intercalated disc protein expression and reduces conduction velocity in arrhythmogenic right ventricular cardiomyopathy. |
title_full_unstemmed |
TMEM43 mutation p.S358L alters intercalated disc protein expression and reduces conduction velocity in arrhythmogenic right ventricular cardiomyopathy. |
title_sort |
tmem43 mutation p.s358l alters intercalated disc protein expression and reduces conduction velocity in arrhythmogenic right ventricular cardiomyopathy. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2014 |
url |
https://doi.org/10.1371/journal.pone.0109128 https://doaj.org/article/81dc701f89c5477fb1ceeb469e49c9d7 |
geographic |
Canada |
geographic_facet |
Canada |
genre |
Newfoundland |
genre_facet |
Newfoundland |
op_source |
PLoS ONE, Vol 9, Iss 10, p e109128 (2014) |
op_relation |
http://europepmc.org/articles/PMC4208740?pdf=render https://doaj.org/toc/1932-6203 1932-6203 doi:10.1371/journal.pone.0109128 https://doaj.org/article/81dc701f89c5477fb1ceeb469e49c9d7 |
op_doi |
https://doi.org/10.1371/journal.pone.0109128 |
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PLoS ONE |
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9 |
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10 |
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e109128 |
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1766109489751130112 |