Understanding the molecular mechanisms of arrhythmogenic right ventricular cardiomyopathy caused by TMEM43 p.S358L mutation

Porter, Zachary G. (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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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.

Item Type: Thesis (Masters)
URI: http://research.library.mun.ca/id/eprint/15891
Item ID: 15891
Additional Information: Includes bibliographical references (pages 115-137) -- Restricted until December 31, 2024
Keywords: TMEM43, arrhythmogenic right ventricular cardiomyopathy, Newfoundland and Labrador, iPSCs
Department(s): Medicine, Faculty of > Biomedical Sciences
Date: October 2022
Date Type: Submission
Digital Object Identifier (DOI): https://doi.org/10.48336/Q6GA-HT87
Medical Subject Heading: Arrhythmogenic Right Ventricular Dysplasia; Myocardium; Arrhythmias, Cardiac; Mutation; Newfoundland and Labrador

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