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Open AccessArticle

Distinct Myocardial Transcriptomic Profiles of Cardiomyopathies Stratified by the Mutant Genes

1
Erich and Hanna Klessmann Institute, Clinic for Thoracic and Cardiovascular Surgery, Heart and Diabetes Centre NRW, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany
2
Center for Biotechnology (CeBiTec), Bielefeld University, 33615 Bielefeld, Germany
3
Graduate School DILS, Bielefeld Institute for Bioinformatics Infrastructure (BIBI), Bielefeld University, 33615 Bielefeld, Germany
4
Department of Medicine, Integrated Cardio Metabolic Centre (ICMC), Heart and Vascular Theme, Karolinska Institutet, 141 57 Huddinge, Sweden
5
Bioscience, Cardiovascular, Renal & Metabolism, BioPharmaceuticals R&D, AstraZeneca, 431 83 Gothenburg, Sweden
*
Authors to whom correspondence should be addressed.
Ralph Knöll and Hendrik Milting are co-senior authors.
Genes 2020, 11(12), 1430; https://doi.org/10.3390/genes11121430
Received: 27 October 2020 / Revised: 24 November 2020 / Accepted: 25 November 2020 / Published: 28 November 2020
(This article belongs to the Special Issue Cardiovascular Genetics)
Cardiovascular diseases are the number one cause of morbidity and mortality worldwide, but the underlying molecular mechanisms remain not well understood. Cardiomyopathies are primary diseases of the heart muscle and contribute to high rates of heart failure and sudden cardiac deaths. Here, we distinguished four different genetic cardiomyopathies based on gene expression signatures. In this study, RNA-Sequencing was used to identify gene expression signatures in myocardial tissue of cardiomyopathy patients in comparison to non-failing human hearts. Therefore, expression differences between patients with specific affected genes, namely LMNA (lamin A/C), RBM20 (RNA binding motif protein 20), TTN (titin) and PKP2 (plakophilin 2) were investigated. We identified genotype-specific differences in regulated pathways, Gene Ontology (GO) terms as well as gene groups like secreted or regulatory proteins and potential candidate drug targets revealing specific molecular pathomechanisms for the four subtypes of genetic cardiomyopathies. Some regulated pathways are common between patients with mutations in RBM20 and TTN as the splice factor RBM20 targets amongst other genes TTN, leading to a similar response on pathway level, even though many differentially expressed genes (DEGs) still differ between both sample types. The myocardium of patients with mutations in LMNA is widely associated with upregulated genes/pathways involved in immune response, whereas mutations in PKP2 lead to a downregulation of genes of the extracellular matrix. Our results contribute to further understanding of the underlying molecular pathomechanisms aiming for novel and better treatment of genetic cardiomyopathies. View Full-Text
Keywords: cardiomyopathy; lamin A/C; RNA binding motif protein 20; titin; plakophilin 2; DCM; ARVC cardiomyopathy; lamin A/C; RNA binding motif protein 20; titin; plakophilin 2; DCM; ARVC
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MDPI and ACS Style

Sielemann, K.; Elbeck, Z.; Gärtner, A.; Brodehl, A.; Stanasiuk, C.; Fox, H.; Paluszkiewicz, L.; Tiesmeier, J.; Wlost, S.; Gummert, J.; Albaum, S.P.; Sielemann, J.; Knöll, R.; Milting, H. Distinct Myocardial Transcriptomic Profiles of Cardiomyopathies Stratified by the Mutant Genes. Genes 2020, 11, 1430. https://doi.org/10.3390/genes11121430

AMA Style

Sielemann K, Elbeck Z, Gärtner A, Brodehl A, Stanasiuk C, Fox H, Paluszkiewicz L, Tiesmeier J, Wlost S, Gummert J, Albaum SP, Sielemann J, Knöll R, Milting H. Distinct Myocardial Transcriptomic Profiles of Cardiomyopathies Stratified by the Mutant Genes. Genes. 2020; 11(12):1430. https://doi.org/10.3390/genes11121430

Chicago/Turabian Style

Sielemann, Katharina; Elbeck, Zaher; Gärtner, Anna; Brodehl, Andreas; Stanasiuk, Caroline; Fox, Henrik; Paluszkiewicz, Lech; Tiesmeier, Jens; Wlost, Stefan; Gummert, Jan; Albaum, Stefan P.; Sielemann, Janik; Knöll, Ralph; Milting, Hendrik. 2020. "Distinct Myocardial Transcriptomic Profiles of Cardiomyopathies Stratified by the Mutant Genes" Genes 11, no. 12: 1430. https://doi.org/10.3390/genes11121430

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