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https://www.readbyqxmd.com/read/29438341/characterization-of-ttn-novex-splicing-variants-across-species-and-the-role-of-rbm20-in-novex-specific-exon-splicing
#1
Zhilong Chen, Jiangping Song, Liang Chen, Chaoqun Zhu, Hanfang Cai, Mingming Sun, Allysa Stern, Paul Mozdziak, Ying Ge, Warrie J Means, Wei Guo
Titin ( TTN ) is a major disease-causing gene in cardiac muscle. Titin ( TTN ) contains 363 exons in human encoding various sizes of TTN protein due to alternative splicing regulated mainly by RNA binding motif 20 (RBM20). Three isoforms of TTN protein are produced by mutually exclusive exons 45 (Novex 1), 46 (Novex 2), and 48 (Novex 3). Alternatively splicing in Novex isoforms across species and whether Novex isoforms are associated with heart disease remains completely unknown. Cross-species exon comparison with the mVISTA online tool revealed that exon 45 is more highly conserved across all species than exons 46 and 48...
February 13, 2018: Genes
https://www.readbyqxmd.com/read/29367541/diagnostic-yield-of-whole-exome-sequencing-in-pediatric-dilated-cardiomyopathy
#2
Pamela A Long, Jared M Evans, Timothy M Olson
Dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder characterized by progressive heart failure. DCM typically remains clinically silent until adulthood, yet symptomatic disease can develop in childhood. We sought to identify the genetic basis of pediatric DCM in 15 sporadic and three affected-siblings cases, comprised of 21 affected children (mean age, five years) whose parents had normal echocardiograms (mean age, 39 years). Twelve underwent cardiac transplantation and five died with severe heart failure...
August 8, 2017: Journal of Cardiovascular Development and Disease
https://www.readbyqxmd.com/read/29304022/muscle-specific-mis-splicing-and-heart-disease-exemplified-by-rbm20
#3
REVIEW
Maimaiti Rexiati, Mingming Sun, Wei Guo
Alternative splicing is an essential post-transcriptional process to generate multiple functional RNAs or proteins from a single transcript. Progress in RNA biology has led to a better understanding of muscle-specific RNA splicing in heart disease. The recent discovery of the muscle-specific splicing factor RNA-binding motif 20 (RBM20) not only provided great insights into the general alternative splicing mechanism but also demonstrated molecular mechanism of how this splicing factor is associated with dilated cardiomyopathy...
January 5, 2018: Genes
https://www.readbyqxmd.com/read/29186814/alternative-splicing-of-l-type-cav1-2-calcium-channels-implications-in-cardiovascular-diseases
#4
REVIEW
(no author information available yet)
L-type Cav1.2 calcium channels are the major pathway for Ca2+ influx to initiate the contraction of smooth and cardiac muscles. Alteration of Cav1.2 channel function has been implicated in multiple cardiovascular diseases, such as hypertension and cardiac hypertrophy. Alternative splicing is a post-transcriptional mechanism that expands Cav1.2 channel structures to modify function, pharmacological and biophysical property such as calcium/voltage-dependent inactivation (C/VDI), or to influence its post-translational modulation by interacting proteins such as Galectin-1...
November 24, 2017: Genes
https://www.readbyqxmd.com/read/29029073/clinical-genetics-and-outcome-of-left-ventricular-non-compaction-cardiomyopathy
#5
Farbod Sedaghat-Hamedani, Jan Haas, Feng Zhu, Christian Geier, Elham Kayvanpour, Martin Liss, Alan Lai, Karen Frese, Regina Pribe-Wolferts, Ali Amr, Daniel Tian Li, Omid Shirvani Samani, Avisha Carstensen, Diana Martins Bordalo, Marion Müller, Christine Fischer, Jing Shao, Jing Wang, Ming Nie, Li Yuan, Sabine Haßfeld, Christine Schwartz, Min Zhou, Zihua Zhou, Yanwen Shu, Min Wang, Kai Huang, Qiutang Zeng, Longxian Cheng, Tobias Fehlmann, Philipp Ehlermann, Andreas Keller, Christoph Dieterich, Katrin Streckfuß-Bömeke, Yuhua Liao, Michael Gotthardt, Hugo A Katus, Benjamin Meder
Aims: In this study, we aimed to clinically and genetically characterize LVNC patients and investigate the prevalence of variants in known and novel LVNC disease genes. Introduction: Left ventricular non-compaction cardiomyopathy (LVNC) is an increasingly recognized cause of heart failure, arrhythmia, thromboembolism, and sudden cardiac death. We sought here to dissect its genetic causes, phenotypic presentation and outcome. Methods and results: In our registry with follow-up of in the median 61 months, we analysed 95 LVNC patients (68 unrelated index patients and 27 affected relatives; definite familial LVNC = 23...
October 6, 2017: European Heart Journal
https://www.readbyqxmd.com/read/28962528/editor-s-highlight-the-altered-dna-methylome-of-chronic-doxorubicin-exposure-in-sprague-dawley-rats
#6
Kendra K S Nordgren, Marshall Hampton, Kendall B Wallace
Doxorubicin (DOX) is a widely used treatment for human cancers, but increases the risk of life-threatening congestive heart failure (CHF). DOX-induced mitochondrial damage is cumulative and persistent, similar to that observed clinically for risk of CHF. Recent evidence suggests the persistent nature of this injury is caused by altered regulation of genes important to normal cardiac functioning. We hypothesize that chronic DOX therapy is associated with epigenetic modifications of DNA methylation status, particularly in critical regulators of mitochondrial function and capacity...
October 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28941705/severe-dcm-phenotype-of-patient-harboring-rbm20-mutation-s635a-can-be-modeled-by-patient-specific-induced-pluripotent-stem-cell-derived-cardiomyocytes
#7
Katrin Streckfuss-Bömeke, Malte Tiburcy, Andrey Fomin, Xiaojing Luo, Wener Li, Claudia Fischer, Cemil Özcelik, Andreas Perrot, Samuel Sossalla, Jan Haas, Ramon Oliveira Vidal, Sabine Rebs, Sara Khadjeh, Benjamin Meder, Stefan Bonn, Wolfgang A Linke, Wolfram-Hubertus Zimmermann, Gerd Hasenfuss, Kaomei Guan
The ability to generate patient-specific induced pluripotent stem cells (iPSCs) provides a unique opportunity for modeling heart disease in vitro. In this study, we generated iPSCs from a patient with dilated cardiomyopathy (DCM) caused by a missense mutation S635A in RNA-binding motif protein 20 (RBM20) and investigated the functionality and cell biology of cardiomyocytes (CMs) derived from patient-specific iPSCs (RBM20-iPSCs). The RBM20-iPSC-CMs showed abnormal distribution of sarcomeric α-actinin and defective calcium handling compared to control-iPSC-CMs, suggesting disorganized myofilament structure and altered calcium machinery in CMs of the RBM20 patient...
September 21, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28767663/contribution-of-exome-sequencing-for-genetic-diagnostic-in-arrhythmogenic-right-ventricular-cardiomyopathy-dysplasia
#8
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
https://www.readbyqxmd.com/read/28676430/insulin-regulates-titin-pre-mrna-splicing-through-the-pi3k-akt-mtor-kinase-axis-in-a-rbm20-dependent-manner
#9
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
https://www.readbyqxmd.com/read/28577155/rbm20-a-potential-target-for-treatment-of-cardiomyopathy-via-titin-isoform-switching
#10
REVIEW
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
https://www.readbyqxmd.com/read/28098235/molecular-characterization-of-pediatric-restrictive-cardiomyopathy-from-integrative-genomics
#11
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
https://www.readbyqxmd.com/read/27889803/reducing-rbm20-activity-improves-diastolic-dysfunction-and-cardiac-atrophy
#12
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"
https://www.readbyqxmd.com/read/27737936/titin-forms-circles-regulation-by-heart-failure-and-the-rna-binding-protein-rbm20
#13
Nicolas Jaé, Stefanie Dimmeler
No abstract text is available yet for this article.
October 14, 2016: Circulation Research
https://www.readbyqxmd.com/read/27634429/identification-of-novel-antigens-contributing-to-autoimmunity-in-cardiovascular-diseases
#14
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
https://www.readbyqxmd.com/read/27630136/experimentally-increasing-the-compliance-of-titin-through-rna-binding-motif-20-rbm20-inhibition-improves-diastolic-function-in-a-mouse-model-of-heart-failure-with-preserved-ejection-fraction
#15
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
https://www.readbyqxmd.com/read/27576561/genotype-phenotype-associations-in-dilated-cardiomyopathy-meta-analysis-on-more-than-8000-individuals
#16
REVIEW
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
https://www.readbyqxmd.com/read/27531932/rbm20-regulates-circular-rna-production-from-the-titin-gene
#17
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
https://www.readbyqxmd.com/read/27524973/increased-titin-compliance-reduced-length-dependent-contraction-and-slowed-cross-bridge-kinetics-in-skinned-myocardial-strips-from-rbm-20%C3%AE-rrm-mice
#18
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
https://www.readbyqxmd.com/read/27496873/a-mutation-in-the-glutamate-rich-region-of-rna-binding-motif-protein-20-causes-dilated-cardiomyopathy-through-missplicing-of-titin-and-impaired-frank-starling-mechanism
#19
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
https://www.readbyqxmd.com/read/27470639/alternative-splicing-of-titin-restores-diastolic-function-in-an-hfpef-like-genetic-murine-model-ttn%C3%AE-iajxn
#20
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
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