Rebecca J Noort, Wesam Salman, Camila Fuchs, Ursula Braun, David Pace, Kathleen A Hodgkinson, Jessica L Esseltine
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引用次数: 0
Abstract
Arrhythmogenic cardiomyopathy (ACM) is clinically characterized by ventricular arrhythmias causing sudden cardiac death and fibrofatty replacement of the myocardium, leading to heart failure. One form of ACM is highly prevalent in the Canadian Province of Newfoundland and Labrador (NL) and has earned the moniker, "The Newfoundland Curse". ACM in NL is often caused by a fully penetrant heterozygous missense pathogenic variant in the TMEM43 gene (TMEM43 c.1073C>T; TMEM43 p.S358L). Although the causative variant has been identified, little is known about the function of the TMEM43 protein in cardiomyocytes, how the TMEM43 p.S358L mutation contributes to the development of arrhythmias, or why the disease is more severe in males than in females. To explore the role of TMEM43 in cardiomyocyte function, we generated induced pluripotent stem cells (iPSCs) from two severely affected male Newfoundland patients with ACM (TMEM43 p.S358L). CRISPR-Cas9 was used to genetically "repair" the heterozygous TMEM43 variant in ACM patient iPSCs. ACM patient iPSC-cardiomyocytes (iPSC-CMs) with the TMEM43 p.S358L variant display pro-arrhythmogenic phenotypes in vitro with significantly elevated contraction rates and altered calcium handling, although no obvious gross abnormalities were observed across several major intracellular organelles. GSK3 inhibition significantly increased the protein expression of β-catenin as well as Lamin A/C and ameliorated the proarrhythmic tendencies of ACM patient iPSC-CMs.NEW & NOTEWORTHY This is the first characterization of induced pluripotent stem cell-cardiomyocytes (iPSC-CMs) from Newfoundland patients with ACM. We find that ACM iPSC-CMs exhibit extreme proarrhythmic tendencies that can be normalized with GSK3 inhibition. Importantly, GSK3 inhibition is accompanied by a significant increase in key proteins, such as β-catenin and Lamin A/C, pointing toward a possible mechanism both for disease pathogenesis and therapy via GSK3 inhibitors.
期刊介绍:
The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.