Abstract 18766: Elucidating the Genetic and Pathogenic Mechanisms of Arrhythmogenic Right Ventricular Cardiomyopathy Type 5

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Introduction: Arrhythmogenic ventricular cardiomyopathies (AVC) are familial diseases of heart muscle characterized by frequent and often life-threatening ventricular arrhythmias. A single missense mutation, p.S358L, in the transmembrane protein 43 (TMEM43/LUMA) gene, causes fully penetrant AVC or ARVC5 characterized by sudden cardiac death among young male mutation carriers and fibro-fatty replacement of the myocardium, particularly in the right ventricle. It has been hypothesized that TMEM43 mutations impact function via Ppar signaling, major regulators of adipogenesis.

Hypothesis: Our aim is to delineate phenotype, genetic mechanisms and pathogenesis of Tmem43-S358L mutation-induced AVC in vivo.

Methods: A mutant Tmem43-S358L mouse was created using conventional knock-in technology. Phenotypic and morphohistological analysis of mutant, heterozygous Tmem43WT/S358L and homozygous Tmem43S358L/S358L mice were performed using echocardiography, cardiac MRI and ECG. Comparative gene expression profiles were analyzed in left and right ventricular (LV and RV, respectively) myocardium by Affymetrix Mouse Gene 2.0ST arrays.

Results: Serial echocardiography revealed alterations in cardiac function at 3 months after birth in Tmem43WT/S358L and Tmem43S358L/S358L mutants compared to WT littermates. Cardiac MRI demonstrated decreased RV systolic function in the mutants compared to the WT littermates. Fibrotic remodeling and ultrastructural defects in sarcomeres was observed in both LV and RV myocardium of the mutant mice. Major differences in expression of many heart failure, fibrosis, metabolism, energy production, and fatty acid oxidation associated genes between LV and RV were revealed in Tmem43-S358L mouse hearts. Of interest, differentially disturbed Pparα and Pparγ pathways were identified in RV myocardium versus LV of mutant mice in contrast to WT littermates.

Conclusions: We conclude that Tmem43 is essential for normal cardiac function. The Tmem43-S358L mutation caused alterations in gene expression of numerous cardiomyopathy/heart failure/adipogenesis associated genes, including Pparα and Pparγ. Differentially perturbed Pparα and Pparγ in LV and RV may underlie the RV-dominant phenotype in ARVC5.

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