Abstract 643: Integrated Systems Genetics Analysis of Tmem43 Mouse Model and Murine Genetic Reference Population of Bxd Strains Defines Novel Genetic Modifiers and Pathogenic Mechanisms in Arrhythmogenic Cardiomyopathy

Background: Arrhythmogenic cardiomyopathies (ACMs) are heritable diseases characterized by arrhythmias, related sudden death, fibro-fatty infiltration and progressive heart failure. Although the pathogenic variant p.S358L in TMEM43/ LUMA causes fully penetrant ACM (ARVC5) in patients, little in vivo evidence has been reported and the roles of Tmem43 in normal cardiac function and disease remain obscure and controversial. This study explored Tmem43-associated genetic modifiers using forward, reverse, and systems genetics analyses in vivo . Methods: Microarray of cardiac and jejunal tissues were performed in a newly created Tmem43 S358L knock-in mouse and in forty BXD strains, used as a murine genetic reference population (GRP). Levels of plasma and fecal lipids and Pparγ activities were defined in heart and jejunum of Tmem43 animals. Immunohistochemistry was performed in the myocardium of patients with non-TMEM43 origin ACM. Results: BXD strain cardiac tissues demonstrated high levels of Tmem43 expression that was significantly negatively correlated with heart mass and heart rate, while positively correlated with plasma HDL and LDL levels. Expression of Tmem43 was also significantly (r>0.5, pPpargc1a ( Pcg1a ) in the heart and intestine of BXDs and Tmem43 mutants. In the Tmem43 S358L mouse heart, Tmem43 and Ppargc1a were downregulated resulting in reduced Pparγ activities. Conversely, Tmem43 and Ppars- regulated genes, including Mogat2, responsible for cholesterol, bile acid, and lipid absorption and re-esterification, were upregulated in the jejunum, resulting in elevated lipid absorption in the gut lumen and hyperlipidemia in Tmem43 S358L mutants. Expression of TMEM43 was disrupted in cardiomyocyte intercalated disks in ACM patients’ myocardium in contrast to normal controls. Conclusions: Tmem43 is an essential gene for cardiac and small intestine signaling and function. The S358L-Tmem43 pathogenic variant is significantly associated with downregulation of Tmem43 , Ppagc1a and Ppar γ in the myocardium and upregulation of Pparγ and Pparα signaling in small intestine in vivo . Testing plasma lipid levels and TMEM43 expression in ACM patients may provide critical information for personalized predictive care.