Understanding the molecular mechanisms of arrhythmogenic right ventricular cardiomyopathy caused by TMEM43 p.S358L mutation
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiac disease characterized by fibrofatty infiltration of the myocardium, life-threatening arrhythmias, and sudden cardiac death. Newfoundland and Labrador is home to a substantial founder population with an autosomal dominant mut...
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ftmemorialuniv:oai:research.library.mun.ca:15891 2023-10-01T03:57:38+02:00 Understanding the molecular mechanisms of arrhythmogenic right ventricular cardiomyopathy caused by TMEM43 p.S358L mutation Porter, Zachary G. 2022-10 https://research.library.mun.ca/15891/ unknown Memorial University of Newfoundland Porter, Zachary G. <https://research.library.mun.ca/view/creator_az/Porter=3AZachary_G=2E=3A=3A.html> (2022) Understanding the molecular mechanisms of arrhythmogenic right ventricular cardiomyopathy caused by TMEM43 p.S358L mutation. Masters thesis, Memorial University of Newfoundland. Thesis NonPeerReviewed 2022 ftmemorialuniv 2023-09-03T06:50:27Z Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiac disease characterized by fibrofatty infiltration of the myocardium, life-threatening arrhythmias, and sudden cardiac death. Newfoundland and Labrador is home to a substantial founder population with an autosomal dominant mutation in the transmembrane protein 43 (TMEM43) gene (c.1073C>T; p.S358L), responsible for ARVC type 5. Although we know that this mutation causes ARVC, there is limited information on the TMEM43 protein life cycle, protein-protein interactions, and function. Additionally, it is unknown how the p.S358L mutation affects TMEM43 function, contributes to ARVC, or why it affects only the heart despite being widely expressed. Here I investigate the intracellular trafficking of wild-type TMEM43 in human induced pluripotent stem cells (iPSCs) and iPSC-cardiomyocytes (iPSC-CMs). I find that TMEM43 resides primarily in early endosomes in iPSCs. Interestingly, although TMEM43 remains localized to early endosomes in early contracting iPSC-CMs, it shifts toward the nuclear envelope as iPSC-CMs are cultured in vitro for an extended period of time. CRISPR-Cas9 genetic ablation of the TMEM43 gene has no apparent effects on several intracellular organelles previously shown to be affected by the TMEM43-S358L mutation. However, TMEM43-/- iPSC-CMs exhibit subtle calcium handling aberrations pointing toward a pro-arrhythmic phenotype. Finally, primary ARVC patient dermal fibroblasts show significant changes in the expression of extracellular matrix proteins, which may play a role in the fibrosis seen in ARVC. Together, these studies begin to unravel the basic life cycle and function of the TMEM43 protein in a human-derived cellular model of ARVC. Thesis Newfoundland Memorial University of Newfoundland: Research Repository Newfoundland |
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Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiac disease characterized by fibrofatty infiltration of the myocardium, life-threatening arrhythmias, and sudden cardiac death. Newfoundland and Labrador is home to a substantial founder population with an autosomal dominant mutation in the transmembrane protein 43 (TMEM43) gene (c.1073C>T; p.S358L), responsible for ARVC type 5. Although we know that this mutation causes ARVC, there is limited information on the TMEM43 protein life cycle, protein-protein interactions, and function. Additionally, it is unknown how the p.S358L mutation affects TMEM43 function, contributes to ARVC, or why it affects only the heart despite being widely expressed. Here I investigate the intracellular trafficking of wild-type TMEM43 in human induced pluripotent stem cells (iPSCs) and iPSC-cardiomyocytes (iPSC-CMs). I find that TMEM43 resides primarily in early endosomes in iPSCs. Interestingly, although TMEM43 remains localized to early endosomes in early contracting iPSC-CMs, it shifts toward the nuclear envelope as iPSC-CMs are cultured in vitro for an extended period of time. CRISPR-Cas9 genetic ablation of the TMEM43 gene has no apparent effects on several intracellular organelles previously shown to be affected by the TMEM43-S358L mutation. However, TMEM43-/- iPSC-CMs exhibit subtle calcium handling aberrations pointing toward a pro-arrhythmic phenotype. Finally, primary ARVC patient dermal fibroblasts show significant changes in the expression of extracellular matrix proteins, which may play a role in the fibrosis seen in ARVC. Together, these studies begin to unravel the basic life cycle and function of the TMEM43 protein in a human-derived cellular model of ARVC. |
format |
Thesis |
author |
Porter, Zachary G. |
spellingShingle |
Porter, Zachary G. Understanding the molecular mechanisms of arrhythmogenic right ventricular cardiomyopathy caused by TMEM43 p.S358L mutation |
author_facet |
Porter, Zachary G. |
author_sort |
Porter, Zachary G. |
title |
Understanding the molecular mechanisms of arrhythmogenic right ventricular cardiomyopathy caused by TMEM43 p.S358L mutation |
title_short |
Understanding the molecular mechanisms of arrhythmogenic right ventricular cardiomyopathy caused by TMEM43 p.S358L mutation |
title_full |
Understanding the molecular mechanisms of arrhythmogenic right ventricular cardiomyopathy caused by TMEM43 p.S358L mutation |
title_fullStr |
Understanding the molecular mechanisms of arrhythmogenic right ventricular cardiomyopathy caused by TMEM43 p.S358L mutation |
title_full_unstemmed |
Understanding the molecular mechanisms of arrhythmogenic right ventricular cardiomyopathy caused by TMEM43 p.S358L mutation |
title_sort |
understanding the molecular mechanisms of arrhythmogenic right ventricular cardiomyopathy caused by tmem43 p.s358l mutation |
publisher |
Memorial University of Newfoundland |
publishDate |
2022 |
url |
https://research.library.mun.ca/15891/ |
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Newfoundland |
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Newfoundland |
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Newfoundland |
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Newfoundland |
op_relation |
Porter, Zachary G. <https://research.library.mun.ca/view/creator_az/Porter=3AZachary_G=2E=3A=3A.html> (2022) Understanding the molecular mechanisms of arrhythmogenic right ventricular cardiomyopathy caused by TMEM43 p.S358L mutation. Masters thesis, Memorial University of Newfoundland. |
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