Systems Genetics Analysis of Arrhythmogenic Cardiomyopathy Induced by p.S368L Mutation in Transmembrane Protein 43

Abstract

BackgroundA missense mutation, p.S358L, in the transmembrane protein 43 (TMEM43/LUMA) gene causes arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5). ARVC5 is characterized by sudden cardiac death and fibro‐fatty replacement of the myocardium, particularly, in the right ventricle (RV). It has been hypothesized that the TMEM43 mutation impacts function via Ppar signaling, major regulators of adipogenesis. Little is known regarding the mechanistic basis of the S358L mutation‐induced effects.ObjectivesThe aim of this study is to discover novel pathways and gene networks associated with the clinical phenotype elicited by the S358L mutation in the Tmem43 gene using a systems genetics approach.MethodsThe mutant Tmem43S358L mouse was created using the conventional knock‐in approach. BXD strains were derived from a cross between C57BL/6J (B6) and DBA/2J (D2) mice. Total RNAs were extracted from heart of mutant Tmem43S358L mice and 40 BXD strains, and hybridized to Affymetrix Mouse Gene 2.0ST arrays. Differential expression of gene was analyzed using two‐way ANOVA and t‐test. Genetic correlation, functional enrichment, and co‐expression network were performed using GeneNetwork (http://genenetwork.org) and Webgestalt (http://www.webgestalt.org) online tools, respectively.ResultsWe found highly significant expression of Tmem43 hearts among the BXD strains with broad variability in expression levels suggesting an important role for Tmem43 in the heart. A co‐expression Tmem43‐gene network consisting of 25 highly associated genes was created and includes many cardiomyopathy‐related genes, including Tmem43, Ppargc1a and Jup, that are highly significantly connected with Tmem43 and each other (r>0.5, p< 0.00075). A significant negative correlation (p<0.01) between Tmem43 expression and heart mass and heart rate was also noted. Levels of high‐density lipoprotein (HDL) in plasma in BXD mice was significantly correlated with Tmem43 on a normal or high‐fat diet. Microarray analysis of the myocardium revealed significant downregulation of Ppargc1a and Pparg (p<0.0001) in Tmem43S358L mice hearts compared to WT littermates. Decrease in Ppargc1a was significantly related with the Tmem43 decrease in RV, suggesting direct inhibition of Ppargc1a by S358L‐Tmem43 mutation.ConclusionsWe conclude that Tmem43 is essential for normal cardiac function. The Tmem43‐S358L mutation causes alterations in gene expression of numerous cardiomyopathy‐associated genes, including Jup, Ppargc1a and Pparg, resulting in the development of ARVC5.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.