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Article

The Combined Human Genotype of Truncating TTN and RBM20 Mutations Is Associated with Severe and Early Onset of Dilated Cardiomyopathy

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Herz-und Diabeteszentrum NRW, Universitätsklinikum der Ruhr-Universität Bochum, Klinik für Thorax- und Kardiovaskularchirurgie, Georgstr. 11, D-32545 Bad Oeynhausen, Germany
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Erich und Hanna Klessmann-Institut für Kardiovaskuläre Forschung und Entwicklung, Georgstr. 11, D-32545 Bad Oeynhausen, Germany
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Bioscience, Cardiovascular, Renal & Metabolism, BioPharmaceuticals R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden
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Department of Medicine (MedH), Integrated Cardio Metabolic Centre (ICMC), Heart and Vascular Theme, Karolinska Institute, SE-171 77 Stockholm, Sweden
*
Author to whom correspondence should be addressed.
Academic Editor: Jeanette Erdmann
Genes 2021, 12(6), 883; https://doi.org/10.3390/genes12060883
Received: 7 May 2021 / Revised: 1 June 2021 / Accepted: 5 June 2021 / Published: 8 June 2021
(This article belongs to the Special Issue Recent Advance in Cardiovascular Genetics)
A major cause of heart failure is cardiomyopathies, with dilated cardiomyopathy (DCM) as the most common form. Over 40 genes are linked to DCM, among them TTN and RBM20. Next Generation Sequencing in clinical DCM cohorts revealed truncating variants in TTN (TTNtv), accounting for up to 25% of familial DCM cases. Mutations in the cardiac splicing factor RNA binding motif protein 20 (RBM20) are also known to be associated with severe cardiomyopathies. TTN is one of the major RBM20 splicing targets. Most of the pathogenic RBM20 mutations are localized in the highly conserved arginine serine rich domain (RS), leading to a cytoplasmic mislocalization of mutant RBM20. Here, we present a patient with an early onset DCM carrying a combination of (likely) pathogenic TTN and RBM20 mutations. We show that the splicing of RBM20 target genes is affected in the mutation carrier. Furthermore, we reveal RBM20 haploinsufficiency presumably caused by the frameshift mutation in RBM20. View Full-Text
Keywords: cardiomyopathy; mutation; RBM20; TTN; haploinsufficiency cardiomyopathy; mutation; RBM20; TTN; haploinsufficiency
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MDPI and ACS Style

Gaertner, A.; Bloebaum, J.; Brodehl, A.; Klauke, B.; Sielemann, K.; Kassner, A.; Fox, H.; Morshuis, M.; Tiesmeier, J.; Schulz, U.; Knoell, R.; Gummert, J.; Milting, H. The Combined Human Genotype of Truncating TTN and RBM20 Mutations Is Associated with Severe and Early Onset of Dilated Cardiomyopathy. Genes 2021, 12, 883. https://doi.org/10.3390/genes12060883

AMA Style

Gaertner A, Bloebaum J, Brodehl A, Klauke B, Sielemann K, Kassner A, Fox H, Morshuis M, Tiesmeier J, Schulz U, Knoell R, Gummert J, Milting H. The Combined Human Genotype of Truncating TTN and RBM20 Mutations Is Associated with Severe and Early Onset of Dilated Cardiomyopathy. Genes. 2021; 12(6):883. https://doi.org/10.3390/genes12060883

Chicago/Turabian Style

Gaertner, Anna, Julia Bloebaum, Andreas Brodehl, Baerbel Klauke, Katharina Sielemann, Astrid Kassner, Henrik Fox, Michiel Morshuis, Jens Tiesmeier, Uwe Schulz, Ralph Knoell, Jan Gummert, and Hendrik Milting. 2021. "The Combined Human Genotype of Truncating TTN and RBM20 Mutations Is Associated with Severe and Early Onset of Dilated Cardiomyopathy" Genes 12, no. 6: 883. https://doi.org/10.3390/genes12060883

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