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Joel Fedida, Veronique Fressart, Philippe Charron, Elodie Surget, Tiphaine Hery, Pascale Richard, Erwan Donal, Boris Keren, Guillaume Duthoit, Françoise Hidden-Lucet, Eric Villard, Estelle Gandjbakhch
BACKGROUND: Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) is an inherited cardiomyopathy mainly caused by heterozygous desmosomal gene mutations, the major gene being PKP2. The genetic cause remains unknown in ~50% of probands with routine desmosomal gene screening. The aim of this study was to assess the diagnostic accuracy of whole exome sequencing (WES) in ARVC/D with negative genetic testing. METHODS: WES was performed in 22 patients, all without a mutation identified in desmosomal genes...
2017: PloS One
Chaoqun Zhu, Zhiyong Yin, Bihua Tan, Wei Guo
Titin, a giant sarcomeric protein, is largely responsible for the diastolic properties of the heart. It has two major isoforms, N2B and N2BA due to pre-mRNA splicing regulated mainly by a splicing factor RNA binding motif 20 (RBM20). Mis-splicing of titin pre-mRNA in response to external stimuli may lead to altered ratio of N2B to N2BA, and thus, impaired cardiac contractile function. However, little is known about titin alternative splicing in response to external stimuli. Here, we reported the detailed mechanisms of titin alternative splicing in response to insulin...
September 2017: Biochimica et Biophysica Acta
Wei Guo, Mingming Sun
Cardiomyopathy, also known as heart muscle disease, is an unfavorable condition leading to alterations in myocardial contraction and/or impaired ability of ventricular filling. The onset and development of cardiomyopathy have not currently been well defined. Titin is a giant multifunctional sarcomeric filament protein that provides passive stiffness to cardiomyocytes and has been implicated to play an important role in the origin and development of cardiomyopathy and heart failure. Titin-based passive stiffness can be mainly adjusted by isoform switching and post-translational modifications in the spring regions...
June 2, 2017: Biophysical Reviews
Tara N Rindler, Robert B Hinton, Nathan Salomonis, Stephanie M Ware
Pediatric restrictive cardiomyopathy (RCM) is a genetically heterogeneous heart disease with limited therapeutic options. RCM cases are largely idiopathic; however, even within families with a known genetic cause for cardiomyopathy, there is striking variability in disease severity. Although accumulating evidence implicates both gene expression and alternative splicing in development of dilated cardiomyopathy (DCM), there have been no detailed molecular characterizations of underlying pathways dysregulated in RCM...
January 18, 2017: Scientific Reports
Florian Hinze, Christoph Dieterich, Michael H Radke, Henk Granzier, Michael Gotthardt
Impaired diastolic filling is a main contributor to heart failure with preserved ejection fraction (HFpEF), a syndrome with increasing prevalence and no treatment. Both collagen and the giant sarcomeric protein titin determine diastolic function. Since titin's elastic properties can be adjusted physiologically, we evaluated titin-based stiffness as a therapeutic target. We adjusted RBM20-dependent cardiac isoform expression in the titin N2B knockout mouse with increased ventricular stiffness. A ~50 % reduction of RBM20 activity does not only maintain cardiac filling in diastole but also ameliorates cardiac atrophy and thus improves cardiac function in the N2B-deficient heart...
December 2016: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Nicolas Jaé, Stefanie Dimmeler
No abstract text is available yet for this article.
October 14, 2016: Circulation Research
Anna-Maria Müller, Mariella Bockstahler, Georgi Hristov, Christel Weiß, Andrea Fischer, Sevil Korkmaz-Icöz, Evangelos Giannitsis, Wolfgang Poller, Heinz-Peter Schultheiss, Hugo A Katus, Ziya Kaya
In myocarditis and dilated cardiomyopathy (DCM) patients the immune system may play an important role in disease progression. In this study, we aimed to identify new antigens as a target for autoimmune response that might play a crucial role in these diseases. Therefore, a peptide-array was used to investigate antibody binding profiles in patients with autoimmune myocarditis or DCM compared to healthy controls and thus to identify disease relevant antigens. To analyze the pathogenicity of the identified antigens, an experimental autoimmune myocarditis (EAM) model was used...
December 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Mei Methawasin, Joshua G Strom, Rebecca E Slater, Vanessa Fernandez, Chandra Saripalli, Henk Granzier
BACKGROUND: Left ventricular (LV) stiffening contributes to heart failure with preserved ejection fraction (HFpEF), a syndrome with no effective treatment options. Increasing the compliance of titin in the heart has become possible recently through inhibition of the splicing factor RNA binding motif-20. Here, we investigated the effects of increasing the compliance of titin in mice with diastolic dysfunction. METHODS: Mice in which the RNA recognition motif (RRM) of one of the RNA binding motif-20 alleles was floxed and that expressed the MerCreMer transgene under control of the αMHC promoter (referred to as cRbm20(ΔRRM) mice) were used...
October 11, 2016: Circulation
Elham Kayvanpour, Farbod Sedaghat-Hamedani, Ali Amr, Alan Lai, Jan Haas, Daniel B Holzer, Karen S Frese, Andreas Keller, Katrin Jensen, Hugo A Katus, Benjamin Meder
AIMS: Routine genetic testing in Dilated Cardiomyopathy (DCM) has recently become reality using Next-Generation Sequencing. Several studies have explored the relationship between genotypes and clinical phenotypes to support risk estimation and therapeutic decisions, however, most studies are small or restricted to a few genes. This study provides to our knowledge the first systematic meta-analysis on genotype-phenotype associations in DCM. METHODS AND RESULTS: We retrieved PubMed/Medline literature on genotype-phenotype associations in patients with DCM and mutations in LMNA, PLN, RBM20, MYBPC3, MYH7, TNNT2 and TNNI3...
February 2017: Clinical Research in Cardiology: Official Journal of the German Cardiac Society
Mohsin A F Khan, Yolan J Reckman, Simona Aufiero, Maarten M G van den Hoogenhof, Ingeborg van der Made, Abdelaziz Beqqali, Dave R Koolbergen, Torsten B Rasmussen, Jolanda van der Velden, Esther E Creemers, Yigal M Pinto
RATIONALE: RNA-binding motif protein 20 (RBM20) is essential for normal splicing of many cardiac genes, and loss of RBM20 causes dilated cardiomyopathy. Given its role in splicing, we hypothesized an important role for RBM20 in forming circular RNAs (circRNAs), a novel class of noncoding RNA molecules. OBJECTIVE: To establish the role of RBM20 in the formation of circRNAs in the heart. METHODS AND RESULTS: Here, we performed circRNA profiling on ribosomal depleted RNA from human hearts and identified the expression of thousands of circRNAs, with some of them regulated in disease...
October 14, 2016: Circulation Research
Hannah C Pulcastro, Peter O Awinda, Mei Methawasin, Henk Granzier, Wenji Dong, Bertrand C W Tanner
Titin is a giant protein spanning from the Z-disk to the M-band of the cardiac sarcomere. In the I-band titin acts as a molecular spring, contributing to passive mechanical characteristics of the myocardium throughout a heartbeat. RNA Binding Motif Protein 20 (RBM20) is required for normal titin splicing, and its absence or altered function leads to greater expression of a very large, more compliant N2BA titin isoform in Rbm20 homozygous mice (Rbm20 (ΔRRM) ) compared to wild-type mice (WT) that almost exclusively express the stiffer N2B titin isoform...
2016: Frontiers in Physiology
Abdelaziz Beqqali, Ilse A E Bollen, Torsten B Rasmussen, Maarten M van den Hoogenhof, Hanneke W M van Deutekom, Sebastian Schafer, Jan Haas, Benjamin Meder, Keld E Sørensen, Ralph J van Oort, Jens Mogensen, Norbert Hubner, Esther E Creemers, Jolanda van der Velden, Yigal M Pinto
AIM: Mutations in the RS-domain of RNA-binding motif protein 20 (RBM20) have recently been identified to segregate with aggressive forms of familial dilated cardiomyopathy (DCM). Loss of RBM20 in rats results in missplicing of the sarcomeric gene titin (TTN). The functional and physiological consequences of RBM20 mutations outside the mutational hotspot of RBM20 have not been explored to date. In this study, we investigated the pathomechanism of DCM caused by a novel RBM20 mutation in human cardiomyocytes...
October 2016: Cardiovascular Research
Mathew Bull, Mei Methawasin, Joshua Strom, Pooja Nair, Kirk Hutchinson, Henk Granzier
RATIONALE: Patients with heart failure with preserved ejection fraction (HFpEF) experience elevated filling pressures and reduced ventricular compliance. The splicing factor RNA-binding motif 20 (RBM20) regulates the contour length of titin's spring region and thereby determines the passive stiffness of cardiomyocytes. Inhibition of RBM20 leads to super compliant titin isoforms (N2BAsc) that reduce passive stiffness. OBJECTIVE: To determine the therapeutic potential of upregulating compliant titin isoforms in an HFpEF-like state in the mouse...
September 2, 2016: Circulation Research
Jipeng Ma, Linhe Lu, Jun Ren, Jian Yang
Heart failure is one of the devastating public health problems with high mortality. Among various contributing factors for heart failure, severe dilated cardiomyopathy is the most common indication for cardiac transplantation. Recent evidence revealed that RBM20 mutation represents one main cause for familial dilated cardiomyopathy with a 3% prevalence in all forms of dilated cardiomyopathy. Further scrutiny of molecular mechanisms suggest a role for RBM20 as a functional splicing factor for protein isoform transition, indicating the clinical value of RBM20 mutations in the diagnosis and treatment of heart diseases...
July 1, 2016: Current Pharmaceutical Design
Magdaléna Neřoldová, Viktor Stránecký, Kateřina Hodaňová, Hana Hartmannová, Lenka Piherová, Anna Přistoupilová, Lenka Mrázová, Michal Vrablík, Věra Adámková, Jaroslav A Hubáček, Milan Jirsa, Stanislav Kmoch
AIM: Genetic variants affecting statin uptake, metabolism or predisposing to muscular diseases may confer susceptibility to statin-induced myopathy. Besides the SLCO1B1 rs4149056 genotype, common genetic variants do not seem to determine statin-associated myopathy. Here we aimed to address the potential role of rare variants. METHODS: We performed whole exome sequencing in 88 individuals suffering from statin-associated myopathy and assessed the burden of rare variants using candidate-gene and exome-wide association analysis...
August 2016: Pharmacogenomics
S P Wyles, S C Hrstka, S Reyes, A Terzic, T M Olson, T J Nelson
For inherited cardiomyopathies, abnormal sensitivity to intracellular calcium (Ca(2+) ), incurred from genetic mutations, initiates subsequent molecular events leading to pathological remodeling. Here, we characterized the effect of β-adrenergic stress in familial dilated cardiomyopathy (DCM) using human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) from a patient with RBM20 DCM. Our findings suggest that β-adrenergic stimulation accelerated defective Ca(2+) homeostasis, apoptotic changes, and sarcomeric disarray in familial DCM hiPSC-CMs...
June 2016: Clinical and Translational Science
Saranya P Wyles, Xing Li, Sybil C Hrstka, Santiago Reyes, Saji Oommen, Rosanna Beraldi, Jessica Edwards, Andre Terzic, Timothy M Olson, Timothy J Nelson
Dilated cardiomyopathy (DCM) is a leading cause of heart failure. In families with autosomal-dominant DCM, heterozygous missense mutations were identified in RNA-binding motif protein 20 (RBM20), a spliceosome protein induced during early cardiogenesis. Dermal fibroblasts from two unrelated patients harboring an RBM20 R636S missense mutation were reprogrammed to human induced pluripotent stem cells (hiPSCs) and differentiated to beating cardiomyocytes (CMs). Stage-specific transcriptome profiling identified differentially expressed genes ranging from angiogenesis regulator to embryonic heart transcription factor as initial molecular aberrations...
January 15, 2016: Human Molecular Genetics
Yue Zhao, Yue Feng, Yun-Mei Zhang, Xiao-Xue Ding, Yu-Zhu Song, A-Mei Zhang, Li Liu, Hong Zhang, Jia-Huan Ding, Xue-Shan Xia
Dilated cardiomyopathy (DCM) is a major cause of sudden cardiac death and heart failure, and it is characterized by genetic and clinical heterogeneity, even for some patients with a very poor clinical prognosis; in the majority of cases, DCM necessitates a heart transplant. Genetic mutations have long been considered to be associated with this disease. At present, mutations in over 50 genes related to DCM have been documented. This study was carried out to elucidate the characteristics of gene mutations in patients with DCM...
December 2015: International Journal of Molecular Medicine
Stephan Waldmüller, Christopher Schroeder, Marc Sturm, Thomas Scheffold, Kerstin Imbrich, Sandra Junker, Christian Frische, Michael Hofbeck, Peter Bauer, Michael Bonin, Meinrad Gawaz, Michael Gramlich
With the implementation of high-throughput sequencing protocols, the exhaustive scanning of known and candidate disease genes has become a feasible approach to genetic testing of patients with cardiomyopathy. A primary objective of the present study was to assess the performance characteristics of a 46-gene next-generation sequencing (NGS) assay that targets well-established cardiomyopathy genes. A total of 25 samples were analyzed. Twelve of those had previously been sequenced using resequencing arrays and served as reference samples for the assessment of the assay's performance characteristics...
October 2015: Molecular and Cellular Probes
Cornelis J Weeland, Maarten M van den Hoogenhof, Abdelaziz Beqqali, Esther E Creemers
Driven by rapidly evolving technologies in next-generation sequencing, alternative splicing has emerged as a crucial layer in gene expression, greatly expanding protein diversity and governing complex biological processes in the cardiomyocyte. At the core of cardiac contraction, the physical properties of the sarcomere are carefully orchestrated through alternative splicing to fit the varying demands on the heart. By the recent discovery of RBM20 and RBM24, two major heart and skeletal muscle-restricted splicing factors, it became evident that alternative splicing events in the heart occur in regulated networks rather than in isolated events...
April 2015: Journal of Molecular and Cellular Cardiology
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