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A Premature Termination Codon Mutation in MYBPC3 Causes Hypertrophic Cardiomyopathy via Chronic Activation of Nonsense-Mediated Decay

Published on Feb 5, 2019in Circulation23.054
· DOI :10.1161/circulationaha.118.034624
Timon Seeger10
Estimated H-index: 10
(Stanford University),
Rajani Shrestha4
Estimated H-index: 4
(Stanford University)
+ 16 AuthorsJoseph C. Wu91
Estimated H-index: 91
(Stanford University)
Abstract
Background: Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in myosin-binding protein C3 (MYBPC3) resulting in a premature termination codon (PTC). The underlying mechanisms of ...
  • References (24)
  • Citations (4)
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References24
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#1Ning Ma (Cardiovascular Institute of the South)H-Index: 4
#2Joe Z. Zhang (Cardiovascular Institute of the South)H-Index: 4
Last. Joseph C. Wu (Cardiovascular Institute of the South)H-Index: 91
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Background: The progression toward low-cost and rapid next-generation sequencing has uncovered a multitude of variants of uncertain significance (VUS) in both patients and asymptomatic “healthy” in...
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#1Priyanka Garg (Cardiovascular Institute of the South)H-Index: 6
#2Angelos Oikonomopoulos (Cardiovascular Institute of the South)H-Index: 6
Last. Joseph C. Wu (Cardiovascular Institute of the South)H-Index: 91
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Abstract Background The long QT syndrome (LQTS) is an arrhythmogenic disorder of QT interval prolongation that predisposes patients to life-threatening ventricular arrhythmias such as Torsades de pointes and sudden cardiac death. Clinical genetic testing has emerged as the standard of care to identify genetic variants in patients suspected of having LQTS. However, these results are often confounded by the discovery of variants of uncertain significance (VUS), for which there is insufficient evid...
18 CitationsSource
#1Maksymilian Prondzynski (UHH: University of Hamburg)H-Index: 8
#2Elisabeth Krämer (UHH: University of Hamburg)H-Index: 12
Last. Lucie Carrier (UHH: University of Hamburg)H-Index: 44
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Gene therapy is a promising option for severe forms of genetic diseases. We previously provided evidence for the feasibility of trans -splicing, exon skipping, and gene replacement in a mouse model of hypertrophic cardiomyopathy (HCM) carrying a mutation in MYBPC3 , encoding cardiac myosin-binding protein C (cMyBP-C). Here we used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from an HCM patient carrying a heterozygous c.1358-1359insC MYBPC3 mutation and from a healthy d...
20 CitationsSource
#1K. Breckwoldt (UHH: University of Hamburg)H-Index: 7
#2David Letuffe-Brenière (UHH: University of Hamburg)H-Index: 2
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This protocol describes how to generate defined embryoid bodies and subsequent standardized beating engineered heart tissue from human iPSCs using small molecules.
40 CitationsSource
#1Ioannis Karakikes (Stanford University)H-Index: 27
#2Vittavat Termglinchan (Stanford University)H-Index: 9
Last. Joseph C. Wu (Stanford University)H-Index: 91
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Rationale: Targeted genetic engineering using programmable nucleases such as transcription activator–like effector nucleases (TALENs) is a valuable tool for precise, site-specific genetic modification in the human genome. Objective: The emergence of novel technologies such as human induced pluripotent stem cells (iPSCs) and nuclease-mediated genome editing represent a unique opportunity for studying cardiovascular diseases in vitro. Methods and Results: By incorporating extensive literature and ...
19 CitationsSource
#1Vittavat Termglinchan (Stanford University)H-Index: 9
#2Timon Seeger (Stanford University)H-Index: 10
Last. Ioannis Karakikes (Stanford University)H-Index: 27
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Precision genome engineering is rapidly advancing the application of the induced pluripotent stem cells (iPSCs) technology for in vitro disease modeling of cardiovascular diseases. Targeted genome editing using engineered nucleases is a powerful tool that allows for reverse genetics, genome engineering, and targeted transgene integration experiments to be performed in a precise and predictable manner. However, nuclease-mediated homologous recombination is an inefficient process. Herein, we descr...
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#1Adam S. Helms (UM: University of Michigan)H-Index: 7
#2Francisco J. Alvarado (UM: University of Michigan)H-Index: 5
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Background: Aberrant calcium signaling may contribute to arrhythmias and adverse remodeling in hypertrophic cardiomyopathy (HCM). Mutations in sarcomere genes may distinctly alter calcium handling pathways. Methods: We analyzed gene expression, protein levels, and functional assays for calcium regulatory pathways in human HCM surgical samples with (n=25) and without (n=10) sarcomere mutations compared with control hearts (n=8). Results: Gene expression and protein levels for calsequestrin, L-typ...
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#1Elena Matsa (Stanford University)H-Index: 20
#2Paul W. BurridgeH-Index: 25
Last. Joseph C. Wu (Stanford University)H-Index: 91
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Summary Understanding individual susceptibility to drug-induced cardiotoxicity is key to improving patient safety and preventing drug attrition. Human induced pluripotent stem cells (hiPSCs) enable the study of pharmacological and toxicological responses in patient-specific cardiomyocytes (CMs) and may serve as preclinical platforms for precision medicine. Transcriptome profiling in hiPSC-CMs from seven individuals lacking known cardiovascular disease-associated mutations and in three isogenic h...
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Nonsense-mediated mRNA decay (NMD) degrades mRNAs with abnormally positioned translation termination codons. It is now becoming apparent that NMD targets mRNAs to enable mammalian cells to adjust their transcriptomes and their proteomes to changing physiological conditions and during diverse cellular processes.
263 CitationsSource
#1Matthew J. Birket (LUMC: Leiden University Medical Center)H-Index: 7
#2Marcelo C. Ribeiro (LUMC: Leiden University Medical Center)H-Index: 6
Last. Christine L. Mummery (LUMC: Leiden University Medical Center)H-Index: 79
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Maximizing baseline function of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is essential for their effective application in models of cardiac toxicity and disease. Here, we aimed to identify factors that would promote an adequate level of function to permit robust single-cell contractility measurements in a human induced pluripotent stem cell (hiPSC) model of hypertrophic cardiomyopathy (HCM). A simple screen revealed the collaborative effects of thyroid hormone, IGF-1 and the ...
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Cited By4
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#1Claudia Sacchetto (UM: Maastricht University)
#1Claudia SacchettoH-Index: 1
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In the last decade, the generation of cardiac disease models based on human-induced pluripotent stem cells (hiPSCs) has become of common use, providing new opportunities to overcome the lack of appropriate cardiac models. Although much progress has been made toward the generation of hiPSC-derived cardiomyocytes (hiPS-CMs), several lines of evidence indicate that two-dimensional (2D) cell culturing presents significant limitations, including hiPS-CMs immaturity and the absence of interaction betw...
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#1Leili Rohani (U of C: University of Calgary)H-Index: 3
#2Pranav Machiraju (U of C: University of Calgary)H-Index: 1
Last. Steven C. GreenwayH-Index: 8
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Abstract Background The dilated cardiomyopathy with ataxia syndrome (DCMA) is an understudied autosomal recessive disease caused by loss-of-function mutations in the poorly characterized gene DNAJC19. Clinically, DCMA is commonly associated with heart failure and early death in affected children through an unknown mechanism. DCMA has been linked to Barth syndrome, a rare but well-studied disorder caused by deficient maturation of cardiolipin (CL), a key mitochondrial membrane phospholipid. Metho...
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#1Eva Vermersch (University of Paris)H-Index: 1
#2Charlène Jouve (University of Paris)H-Index: 1
Last. Jean-Sébastien Hulot (University of Paris)H-Index: 43
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: Cardiovascular diseases are among the main causes of morbidity and mortality in Western countries and considered as a leading public health issue. Therefore, there is a strong need for new disease models to support the development of novel therapeutics approaches. The successive improvement of genome editing tools with zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and more recently with clustered regularly interspaced short palindromic repeats (CRISPR)...
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Abstract During the past decade, developments in genome editing technology have fundamentally transformed biomedical research. In particular, the CRISPR/Cas9 system has been extensively applied because of its simplicity and ability to alter genomic sequences within living organisms, and an ever increasing number of CRISPR/Cas9-based molecular tools are being developed for a wide variety of applications. While genome editing tools have been used for many aspects of biological research, they also ...
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: Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy, historically believed to affect 1 of 500 people. MYBPC3 pathogenic variations are the most frequent cause of familial HCM and more than 90% of them introduce a premature termination codon. The current study aims to determine the prevalence of deep intronic MYBPC3 pathogenic variations that could lead to splice mutations. To improve molecular diagnosis, a next-generation sequencing (NGS) workflow based on whole MYBPC...
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#1Adam S. HelmsH-Index: 7
#1Adam S. HelmsH-Index: 8
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Mutations in cardiac myosin binding protein C (MyBP-C, encoded by MYBPC3) are the most common cause of hypertrophic cardiomyopathy (HCM). Most MYBPC3 mutations result in premature termination codons (PTCs) that cause RNA degradation and a reduction of MyBP-C in HCM patient hearts. However, a reduction in MyBP-C has not been consistently observed in MYBPC3-mutant induced pluripotent stem cell cardiomyocytes (iPSCMs). To determine early MYBPC3 mutation effects, we used patient and genome-engineere...
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Cardiomyopathies are diseases of heart muscle, a significant percentage of which are genetic in origin. Cardiomyopathies can be classified as dilated, hypertrophic, restrictive, arrhythmogenic right ventricular or left ventricular non-compaction, although mixed morphologies are possible. A subset of neuromuscular disorders, notably Duchenne and Becker muscular dystrophies, are also characterized by cardiomyopathy aside from skeletal myopathy. The global burden of cardiomyopathies is certainly hi...
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#1David T. Paik (Cardiovascular Institute of the South)H-Index: 6
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Human induced pluripotent stem cells (iPSCs) have emerged as an effective platform for regenerative therapy, disease modeling, and drug discovery. iPSCs allow for the production of limitless supply of patient-specific somatic cells that enable advancement in cardiovascular precision medicine. Over the past decade, researchers have developed protocols to differentiate iPSCs to multiple cardiovascular lineages, as well as to enhance the maturity and functionality of these cells. Despite significan...
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Cardiovascular diseases remain the leading cause of death in the developed world, accounting for more than 30% of all deaths. In a large proportion of these patients, acute myocardial infarction is usually the first manifestation, which might further progress to heart failure. In addition, the human heart displays a low regenerative capacity, leading to a loss of cardiomyocytes and persistent tissue scaring, which entails a morbid pathologic sequela. Novel therapeutic approaches are urgently nee...
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#1Gary A. GintantH-Index: 2
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It is now well recognized that many lifesaving oncology drugs may adversely affect the heart and cardiovascular system, including causing irreversible cardiac injury that can result in reduced qual...
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