Background: Broad cellular functions and diseases including muscular dystrophy, arrhythmogenic right ventricular cardiomyopathy (ARVC5) and cancer are associated with transmembrane protein43 (TMEM43/LUMA). Objective: The study aimed to investigate biological roles of TMEM43 through genetic regulation, gene pathways and gene networks, candidate interacting genes and up- or down-stream regulators. Methods: Cardiac transcriptomes from 40 strains of recombinant inbred BXD mice and two parental strains representing murine genetic reference population (GRP) was applied for genetic correlation, functional enrichment and co-expression network analysis using systems genetics approach. The results were validated in a newly created knock-in Tmem43-S358L mutation mouse model (Tmem43S358L) that displayed signs of cardiac dysfunction, resembling ARVC5 phenotype seen in humans. Results: We found high Tmem43 levels among BXDs with broad variability in expression. Expression of Tmem43 highly negatively correlated with heart mass and heart rate among BXDs, while levels of Tmem43 highly positively correlated with plasma high density lipoproteins (HDL). Through finding differentially expressed genes (DEGs) between Tmem43S358L mutant and wild type (Tmem43WT) lines, 18 pathways (out of 42 found in BXDs GRP) that are involved in ARVC, Hypertrophic cardiomyopathy, Dilated cardiomyopathy, Non-alcoholic fatty liver disease, Alzheimer disease, Parkinson disease and Huntington disease were verified. We further constructed Tmem43-mediated gene network, in which Ctnna1, Adcy6, Gnas, Ndufs6 and Uqcrc2 were significantly altered in Tmem43S358L mice vs Tmem43WT controls. Conclusions: Our study defined the importance of Tmem43 for cardiac and metabolism related pathways, suggesting that cardiovascular disease-relevant risk factors may also increase risk of metabolic and neurodegenerative diseases via TMEM43-mediated pathways.

Restrictive cardiomyopathy (RCM), a potentially devastating heart muscle disorder, is characterized by diastolic dysfunction due to abnormal muscle relaxation and myocardial stiffness resulting in restrictive filling of the ventricles. Diastolic dysfunction is often accompanied by left atrial or bi-atrial enlargement and normal ventricular size and systolic function. RCM is the rarest form of cardiomyopathy, accounting for 2-5% of pediatric cardiomyopathy cases, however, survival rates have been reported to be 82%, 80%, and 68% at 1-, 2-, and 5-years after diagnosis, respectively. RCM can be idiopathic, familial, or secondary to a systemic disorder, such as amyloidosis, sarcoidosis, and hereditary hemochromatosis. Approximately 30% of cases are familial RCM, and the genes that have been linked to RCM are cTnT, cTnI, MyBP-C, MYH7, MYL2, MYL3, DES, MYPN, TTN, BAG3, DCBLD2, LNMA, and FLNC. Increased Ca 2+ sensitivity, sarcomere disruption, and protein aggregates are some of the few mechanisms of pathogenesis that have been revealed by studies utilizing cell lines and animal models. Additional exploration into the pathogenesis of RCM is necessary to create novel therapeutic strategies to reverse restrictive cardiomyopathic phenotypes.

Studies showed that the gastrointestinal (GI) tract is one of the most important pathways for SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19). As SARS-CoV-2 cellular entry depends on the ACE2 receptor and TMPRSS2 priming of the spike protein, it is important to understand the molecular mechanisms through which these two proteins and their cognate transcripts interact and influence the pathogenesis of COVID-19. In this study, we quantified the expression, associations, genetic modulators, and molecular pathways for Tmprss2 and Ace2 mRNA expressions in GI tissues using a systems genetics approach and the expanded family of highly diverse BXD mouse strains. The results showed that both Tmprss2 and Ace2 are highly expressed in GI tissues with significant covariation. We identified a significant expression quantitative trait locus on chromosome 7 that controls the expression of both Tmprss2 and Ace2. Dhx32 was found to be the strongest candidate in this interval. Co-expression network analysis demonstrated that both Tmprss2 and Ace2 were located at the same module that is significantly associated with other GI-related traits. Protein–protein interaction analysis indicated that hub genes in this module are linked to circadian rhythms. Collectively, our data suggested that genes with circadian rhythms of expression may have an impact on COVID-19 disease, with implications related to the timing and treatment of COVID-19.