A myomesin mutation associated with hypertrophic cardiomyopathy deteriorates dimerisation properties

Siegert, Romy; Perrot, Andreas; Keller, Sandro; Behlke, Joachim; Michalewska-Włudarczyk, Aleksandra; Wycisk, Anna; Tendera, Michał; Morano, Ingo; Özcelik, C.

doi:10.1016/j.bbrc.2011.01.056

Cited by 33 publications

(43 citation statements)

References 28 publications

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“…The myomesins are elastic proteins mostly located in the center of the M-band [39] and may have implications for hypertrophic cardiomyopathy [40]. Glutathione S-transferase P is involved in the regeneration of reduced thiols [41] and therefore the relatively lower levels may indicate disruption to oxidative state in the hypertrophic myocardium.…”

Section: Discussionmentioning

confidence: 99%

The effect of disease on human cardiac protein expression profiles in paired samples from right and left ventricles

et al. 2014

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BackgroundCardiac diseases (e.g. coronary and valve) are associated with ventricular cellular remodeling. However, ventricular biopsies from left and right ventricles from patients with different pathologies are rare and thus little is known about disease-induced cellular remodeling in both sides of the heart and between different diseases. We hypothesized that the protein expression profiles between right and left ventricles of patients with aortic valve stenosis (AVS) and patients with coronary artery disease (CAD) are different and that the protein profile is different between the two diseases. Left and right ventricular biopsies were collected from patients with either CAD or AVS. The biopsies were processed for proteomic analysis using isobaric tandem mass tagging and analyzed by reverse phase nano-LC-MS/MS. Western blot for selected proteins showed strong correlation with proteomic analysis.ResultsProteomic analysis between ventricles of the same disease (intra-disease) and between ventricles of different diseases (inter-disease) identified more than 500 proteins detected in all relevant ventricular biopsies. Comparison between ventricles and disease state was focused on proteins with relatively high fold (±1.2 fold difference) and significant (P < 0.05) differences. Intra-disease protein expression differences between left and right ventricles were largely structural for AVS patients and largely signaling/metabolism for CAD. Proteins commonly associated with hypertrophy were also different in the AVS group but with lower fold difference. Inter-disease differences between left ventricles of AVS and CAD were detected in 9 proteins. However, inter-disease differences between the right ventricles of CAD and AVS patients were associated with differences in 73 proteins. The majority of proteins which had a significant difference in one ventricle compared to the other pathology also had a similar trend in the adjacent ventricle.ConclusionsThis work demonstrates for the first time that left and right ventricles have a different proteome and that the difference is dependent on the type of disease. Inter-disease differential expression was more prominent for right ventricles. The finding that a protein change in one ventricle was often associated with a similar trend in the adjacent ventricle for a large number of proteins suggests cross-talk proteome remodeling between adjacent ventricles.

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Section: Discussionmentioning

confidence: 99%

The effect of disease on human cardiac protein expression profiles in paired samples from right and left ventricles

et al. 2014

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“…Associations with hypertrophic cardiomyopathy (HCM)were rare, and included Arg740Leu, which increases titin-α actinin binding, and Ser3799Tyr, which increases four and a half LIM protein 2 (FHL2) binding. 43,45 Interestingly, mutations of genes encoding proteins that interact with titin, including myomesin 49 , cardiac ankyrin repeat protein (ANKRD-1) 50,51 , FHL2 52 and telethonin (TCAP) 53 are associated with both HCM and DCM.…”

Section: Titin Mutations and Diseasementioning

confidence: 99%

Cardiac Titin and Heart Disease

LeWinter

Granzier

2014

Journal of Cardiovascular Pharmacology

124

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The giant sarcomeric protein titin is a key determinant of myocardial passive stiffness and stress sensitive signaling. Titin stiffness is modulated by isoform variation, phosphorylation by protein kinases and possibly oxidative stress through disulfide bond formation. Titin has also emerged as an important human disease gene. Early studies in patients with dilated cardiomyopathy (DCM) revealed shifts toward more compliant isoforms, an adaptation that offsets increases in passive stiffness based in the extracellular matrix. Similar shifts are observed in heart failure with preserved ejection fraction (HFpEF). In contrast, hypophosphorylation of PKA/G sites contributes to a net increase in cardiomyocyte resting tension in HFpEF. More recently, titin mutations have been recognized as the most common etiology of inherited DCM. In addition, some DCM-causing mutations affect RBM20, a titin splice factor. Titin mutations are a rare cause of hypertrophic cardiomyopathy (HCM) and also underlie some cases of arrhythmogenic right ventricular dysplasia. Finally, mutations of genes encoding proteins that interact with and/or bind to titin are responsible for both DCM and HCM. Targeting titin as a therapeutic strategy is in its infancy, but could potentially involve manipulation of isoforms, post-translational modifications, and up-regulation of normal protein in patients with disease causing mutations.

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“…Etv5 codes for a transcription factor involved in skeletal muscle acetylcholine-gated channel clustering at neuromuscular junctions; it belongs to the most abundant Ets transcripts in the early embryonic mouse heart [25] and gene targeting in zebrafish suggested a role in embryonic cardiac patterning [26]. Myom2 codes for myomesin, the major component of myofibrillar M bands in vertebrates; human MYOM2 mutations are associated with hypertrophic cardiomyopathy [27], while overexpression of EH-myomesin, the predominant MYOM2 isoform in the embryonic heart, has been suggested as a biomarker of dilated cardiomyopathy [28]. Synpo2l encodes a cytoskeletal, heart-enriched, actin-associated protein; knock-down in zebrafish causes aberrant cardiac and skeletal muscle development and function [29], whereas human variants are associated with atrial fibrillation [30].…”

Section: Resultsmentioning

confidence: 99%

RNAseq analysis of heart tissue from mice treated with atenolol and isoproterenol reveals a reciprocal transcriptional response

et al. 2016

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BackgroundThe transcriptional response to many widely used drugs and its modulation by genetic variability is poorly understood. Here we present an analysis of RNAseq profiles from heart tissue of 18 inbred mouse strains treated with the β-blocker atenolol (ATE) and the β-agonist isoproterenol (ISO).ResultsDifferential expression analyses revealed a large set of genes responding to ISO (n = 1770 at FDR = 0.0001) and a comparatively small one responding to ATE (n = 23 at FDR = 0.0001). At a less stringent definition of differential expression, the transcriptional responses to these two antagonistic drugs are reciprocal for many genes, with an overall anti-correlation of r = −0.3. This trend is also observed at the level of most individual strains even though the power to detect differential expression is significantly reduced. The inversely expressed gene sets are enriched with genes annotated for heart-related functions. Modular analysis revealed gene sets that exhibit coherent transcription profiles across some strains and/or treatments. Correlations between these modules and a broad spectrum of cardiovascular traits are stronger than expected by chance. This provides evidence for the overall importance of transcriptional regulation for these organismal responses and explicits links between co-expressed genes and the traits they are associated with. Gene set enrichment analysis of differentially expressed groups of genes pointed to pathways related to heart development and functionality.ConclusionsOur study provides new insights into the transcriptional response of the heart to perturbations of the β-adrenergic system, implicating several new genes that had not been associated to this system previously.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3059-6) contains supplementary material, which is available to authorized users.

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A myomesin mutation associated with hypertrophic cardiomyopathy deteriorates dimerisation properties

Cited by 33 publications

References 28 publications

The effect of disease on human cardiac protein expression profiles in paired samples from right and left ventricles

The effect of disease on human cardiac protein expression profiles in paired samples from right and left ventricles

Cardiac Titin and Heart Disease

RNAseq analysis of heart tissue from mice treated with atenolol and isoproterenol reveals a reciprocal transcriptional response

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