Cardiac myosin-binding protein C (MYBPC3) in cardiac pathophysiology.

Published on Dec 1, 2015in Gene 2.50
· DOI :10.1016/j.gene.2015.09.008
Lucie Carrier42
Estimated H-index: 42
(University of Hamburg),
Giulia Mearini15
Estimated H-index: 15
(University of Hamburg)
+ 1 AuthorsFriederike Cuello6
Estimated H-index: 6
(University of Hamburg)
Abstract
Abstract More than 350 individual MYPBC3 mutations have been identified in patients with inherited hypertrophic cardiomyopathy (HCM), thus representing 40–50% of all HCM mutations, making it the most frequently mutated gene in HCM. HCM is considered a disease of the sarcomere and is characterized by left ventricular hypertrophy, myocyte disarray and diastolic dysfunction. MYBPC3 encodes for the thick filament associated protein cardiac myosin-binding protein C (cMyBP-C), a signaling node in cardiac myocytes that contributes to the maintenance of sarcomeric structure and regulation of contraction and relaxation. This review aims to provide a succinct overview of how mutations in MYBPC3 are considered to affect the physiological function of cMyBP-C, thus causing the deleterious consequences observed in HCM patients. Importantly, recent advances to causally treat HCM by repairing MYBPC3 mutations by gene therapy are discussed here, providing a promising alternative to heart transplantation for patients with a fatal form of neonatal cardiomyopathy due to bi-allelic truncating MYBPC3 mutations.
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References152
Published on May 1, 1995in The EMBO Journal 10.56
Mathias Gautel54
Estimated H-index: 54
,
Orsetta Zuffardi57
Estimated H-index: 57
+ 1 AuthorsSiegfried Labeit55
Estimated H-index: 55
Abstract Cardiac myosin binding protein-C (cardiac MyBP-C, cardiac C protein) belongs to a family of proteins implicated in both regulatory and structural functions of striated muscle. For the cardiac isoform, regulatory phosphorylation in vivo by cAMP-dependent protein kinase (PKA) upon adrenergic stimulation is linked to modulation of cardiac contraction. The sequence of human cardiac MyBP-C now reveals regulatory motifs specific for this isoform. Site-directed mutagenesis identifies a LAGGGRR...
308 Citations Source Cite
Published on Feb 25, 1982in Journal of Biological Chemistry 4.01
H C Hartzell1
Estimated H-index: 1
,
L Titus1
Estimated H-index: 1
Abstract The purpose of this investigation was to examine the effects of beta-adrenergic and muscarinic cholinergic agonists on protein phosphorylation in intact frog atrium. beta-Adrenergic agonists increase and muscarinic agonists decrease 32P incorporation into a 165,000-dalton (165K) protein within less than 1 min. The concentrations of isoproterenol that produce increases in 32P incorporation into the 165K protein and in systolic tension are similar. Further, the changes in 32P incorporatio...
72 Citations
Published on Dec 25, 1984in Journal of Biological Chemistry 4.01
H C Hartzell1
Estimated H-index: 1
,
D B Glass1
Estimated H-index: 1
Abstract C-protein, a component of the thick filament of striated muscles, becomes phosphorylated in response to beta-adrenergic receptor stimulation and dephosphorylated in response to cholinergic receptor stimulation in heart. We have purified C-protein in high yield from cardiac muscle (approximately 50% yield: 0.3 mg of C-protein/g of frozen chicken heart). C-protein has a molecular weight on sodium dodecyl sulfate polyacrylamide gels of 155,000 but the native protein migrates as a globular ...
124 Citations
Published on Mar 1, 1997in Circulation Research 15.21
Lucie Carrier42
Estimated H-index: 42
,
Gisèle Bonne52
Estimated H-index: 52
+ 15 AuthorsSiegfried Labeit35
Estimated H-index: 35
Cardiac myosin binding protein C (MyBP-C) is a sarcomeric protein belonging to the intracellular immunoglobulin superfamily. Its function is uncertain, but for a decade evidence has existed for both structural and regulatory roles. The gene encoding cardiac MyBP-C (MYBPC3) in humans is located on chromosome 11p11.2, and mutations have been identified in this gene in unrelated families with familial hypertrophic cardiomyopathy (FHC). Detailed characterization of the MYBPC3 gene is essential for s...
216 Citations Source Cite
Published on Dec 31, 2012in Circulation Research 15.21
Diederik W.D. Kuster9
Estimated H-index: 9
(Loyola University Chicago),
Vasco Sequeira10
Estimated H-index: 10
+ 10 AuthorsJeroen Demmers47
Estimated H-index: 47
(Erasmus University Medical Center)
Rationale: Cardiac myosin binding protein C (cMyBP-C) regulates cross-bridge cycling kinetics and thereby fine-tunes the rate of cardiac muscle contraction and relaxation. Its effects on cardiac kinetics are modified by phosphorylation. Three phosphorylation sites (Ser275, Ser284, Ser304) have been identified in vivo, all located in the cardiac-specific M-domain of cMyBP-C. However recent work has shown that up to four phosphate groups are present in human cMyBP-C. Objective: To identify and cha...
23 Citations Source Cite
Published on Aug 1, 2007in Journal of Molecular and Cellular Cardiology 5.30
Ali El-Armouche9
Estimated H-index: 9
(University of Hamburg),
Lutz Pohlmann3
Estimated H-index: 3
(University of Hamburg)
+ 6 AuthorsLucie Carrier42
Estimated H-index: 42
(French Institute of Health and Medical Research)
Abstract Cardiac myosin-binding protein-C (cMyBP-C) is an important regulator of cardiac contractility, and its phosphorylation by PKA is a mechanism that contributes to increased cardiac output in response to β-adrenergic stimulation. It is presently unknown whether heart failure alters cMyBP-C phosphorylation. The present study determined the level of phosphorylated cMyBP-C in failing human hearts and in a canine model of pacing-induced heart failure. A polyclonal antibody directed against the...
117 Citations Source Cite
Published on Jan 1, 2012in Heart Rhythm 4.74
Barry J. Maron148
Estimated H-index: 148
,
Martin S. Maron51
Estimated H-index: 51
(Tufts Medical Center),
Christopher Semsarian Fracp Faha Fcsanz45
Estimated H-index: 45
(Royal Prince Alfred Hospital)
Background Risk stratification strategies employing sarcomere gene mutational analysis have proved imprecise in identifying high-risk patients with hypertrophic cardiomyopathy (HCM). Therefore, additional genetic risk markers that reliably determine which patients are predisposed to sudden death are needed. Objective The objective of this study was to determine whether multiple disease-causing sarcomere mutations can be regarded as markers for sudden death in the absence of other conventional ri...
90 Citations Source Cite
Published on May 7, 2015in European Heart Journal 23.43
Jan Haas19
Estimated H-index: 19
(Heidelberg University),
Karen Frese15
Estimated H-index: 15
(Heidelberg University)
+ 57 AuthorsBritta Vogel17
Estimated H-index: 17
(Heidelberg University)
Aim Numerous genes are known to cause dilated cardiomyopathy (DCM). However, until now technological limitations have hindered elucidation of the contribution of all clinically relevant disease genes to DCM phenotypes in larger cohorts. We now utilized next-generation sequencing to overcome these limitations and screened all DCM disease genes in a large cohort. Methods and results In this multi-centre, multi-national study, we have enrolled 639 patients with sporadic or familial DCM. To all samp...
190 Citations Source Cite
Published on Jan 1, 2013in Molecular therapy. Nucleic acids 5.66
Giulia Mearini15
Estimated H-index: 15
(University of Hamburg),
Doreen Stimpel3
Estimated H-index: 3
(University of Hamburg)
+ 11 AuthorsEschenhagenThomas65
Estimated H-index: 65
(University of Hamburg)
RNA trans-splicing has been explored as a therapeutic option for a variety of genetic diseases, but not for cardiac genetic disease. Hypertrophic cardiomyopathy (HCM) is an autosomal-dominant disease, characterized by left ventricular hypertrophy (LVH) and diastolic dysfunction. MYBPC3, encoding cardiac myosin-binding protein C (cMyBP-C) is frequently mutated. We evaluated the 5′-trans-splicing strategy in a mouse model of HCM carrying a Mybpc3 mutation. 5′-trans-splicing was induced between two...
37 Citations Source Cite
Published on Jan 1, 2012in Neonatology 2.69
Nicola Marziliano18
Estimated H-index: 18
,
Piera Angelica Merlini37
Estimated H-index: 37
+ 5 AuthorsSilvio Veronese33
Estimated H-index: 33
Hypertrophic cardiomyopathy (HCM) is a familial, genetically determined, primary cardiomyopathy caused by mutations in genes coding for proteins of the sarcomere, or, less frequently, genes involved in storage diseases. In pediatric settings, pure HCM has an estimated incidence of 4.7 per million children. The disease is often sub-clinical and goes unrecognized mainly because most patients with HCM have only mild symptoms, if any. However, sudden cardiac death, the most dramatic clinical occurre...
18 Citations Source Cite
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  • Citations (41)
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Cited By41
Published on Jan 1, 2016in Cardiovascular Research 6.29
Frederik Flenner6
Estimated H-index: 6
(University of Hamburg),
Felix W. Friedrich12
Estimated H-index: 12
(University of Hamburg)
+ 12 AuthorsF. Weinberger9
Estimated H-index: 9
(University of Hamburg)
Aims Hypertrophic cardiomyopathy (HCM) is often accompanied by increased myofilament Ca2+ sensitivity and diastolic dysfunction. Recent findings indicate increased late Na+ current density in human HCM cardiomyocytes. Since ranolazine has the potential to decrease myofilament Ca2+ sensitivity and late Na+ current, we investigated its effects in an Mybpc3 -targeted knock-in (KI) mouse model of HCM. Methods and results Unloaded sarcomere shortening and Ca2+ transients were measured in KI and wild-...
21 Citations Source Cite
Published on Jan 1, 2016in Structure 4.91
Naveed A. Nadvi7
Estimated H-index: 7
(University of Sydney),
Katharine A. Michie7
Estimated H-index: 7
(University of Sydney)
+ 2 AuthorsJill Trewhella40
Estimated H-index: 40
(University of Sydney)
The structural effects of three missense mutations clinically linked to hypertrophic cardiomyopathy (HCM) and located in the central domains of cardiac myosin-binding protein C (cMyBP-C) have been determined using small-angle scattering, infrared spectroscopy, and nuclear magnetic resonance spectroscopy. Bioinformatics and modeling were used to initially predict the expected structural impacts and assess the broader implications for function based on sequence conservation patterns. The experimen...
3 Citations Source Cite
Published on Jul 1, 2016in Archives of Biochemistry and Biophysics 3.12
Sabine J. van Dijk4
Estimated H-index: 4
(University of Arizona),
Kristina Bezold Kooiker6
Estimated H-index: 6
(Stanford University)
+ 7 AuthorsSamantha P. Harris19
Estimated H-index: 19
(University of Arizona)
Mutations in MYBPC3, the gene encoding cardiac myosin binding protein C (cMyBP-C), are a major cause of hypertrophic cardiomyopathy (HCM). While most mutations encode premature stop codons, missense mutations causing single amino acid substitutions are also common. Here we investigated effects of a single proline for alanine substitution at amino acid 31 (A31P) in the C0 domain of cMyBP-C, which was identified as a natural cause of HCM in cats. Results using recombinant proteins showed that the ...
6 Citations Source Cite
Published on May 1, 2016in The FASEB Journal 5.59
Konstantina Stathopoulou12
Estimated H-index: 12
(University of Hamburg),
Ilka Wittig37
Estimated H-index: 37
(Goethe University Frankfurt)
+ 15 AuthorsEwald Schröder8
Estimated H-index: 8
(King's College London)
Cardiac myosin-binding protein C (cMyBP-C) regulates actin-myosin interaction and thereby cardiac myocyte contraction and relaxation. This physiologic function is regulated by cMyBP-C phosphorylation. In our study, reduced site-specific cMyBP-C phosphorylation coincided with increased S-glutathiolation in ventricular tissue from patients with dilated or ischemic cardiomyopathy compared to nonfailing donors. We used redox proteomics, to identify constitutive and disease-specific S-glutathiolation...
8 Citations Source Cite
Published on Aug 1, 2016in Journal of Molecular and Cellular Cardiology 5.30
Paul J.M. Wijnker12
Estimated H-index: 12
(University of Hamburg),
Felix W. Friedrich12
Estimated H-index: 12
(University of Hamburg)
+ 7 AuthorsLucie Carrier42
Estimated H-index: 42
(University of Hamburg)
Abstract Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease characterized by left ventricular hypertrophy, diastolic dysfunction and myocardial disarray. The most frequently mutated gene is MYBPC3 , encoding cardiac myosin-binding protein-C (cMyBP-C). We compared the pathomechanisms of a truncating mutation (c.2373_2374insG) and a missense mutation (c.1591G>C) in MYBPC3 in engineered heart tissue (EHT). EHTs enable to study the direct effects of mutants without interference of second...
12 Citations Source Cite
Camille Birch3
Estimated H-index: 3
(University of Arizona),
Samantha M. Behunin3
Estimated H-index: 3
(University of Arizona)
+ 5 AuthorsJohn P. Konhilas18
Estimated H-index: 18
(University of Arizona)
We illustrate sex dimorphisms in crossbridge kinetics where male hypertrophic cardiomyopathy hearts displayed an increased while female hypertrophic cardiomyopathy hearts displayed a decreased tension cost. In addition, we have found sex- and mutation-dependent differences in cardiac remodeling at the morphometric, histological, and cellular level.
3 Citations Source Cite
Published on Dec 1, 2016in Journal of Cardiovascular Magnetic Resonance 5.46
Mika Tarkiainen2
Estimated H-index: 2
,
Petri Sipola12
Estimated H-index: 12
(University of Eastern Finland)
+ 6 AuthorsJohanna Kuusisto76
Estimated H-index: 76
(University of Eastern Finland)
Background Previous data suggest that mitral valve leaflets are elongated in hypertrophic cardiomyopathy (HCM), and mitral valve leaflet elongation may constitute a primary phenotypic expression of HCM. Our objective was to measure the length of mitral valve leaflets by cardiovascular magnetic resonance (CMR) in subjects with HCM caused by a Finnish founder mutation in the myosin-binding protein C gene (MYBPC3-Q1061X), carriers of the same mutation without left ventricular hypertrophy, as well a...
8 Citations Source Cite
Published on Sep 1, 2016in Scientific Reports 4.12
Gabriella Captur13
Estimated H-index: 13
,
Carolyn Y. Ho35
Estimated H-index: 35
+ 14 AuthorsJames C. Moon44
Estimated H-index: 44
Hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomeric proteins, the commonest being MYBPC3 encoding myosin-binding protein C. It is characterised by left ventricular hypertrophy but there is an important pre-hypertrophic phenotype with features including crypts, abnormal mitral leaflets and trabeculae. We investigated these during mouse cardiac development using high-resolution episcopic microscopy. In embryonic hearts from wildtype, homozygous (HO) and heterozygous (HET) Mybpc3...
9 Citations Source Cite
Published on Oct 2, 2016in Annals of Medicine 3.01
Johanna Kuusisto76
Estimated H-index: 76
(University of Eastern Finland),
Petri Sipola12
Estimated H-index: 12
+ 1 AuthorsAnita Naukkarinen1
Estimated H-index: 1
AbstractHypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, with the prevalence of about 1/500. During the last two decades, the knowledge of the etiology, pathogenesis, risk stratification and prevention of sudden death in HCM has substantially advanced. Most often, HCM is familial and caused by mutations in sarcomere genes, inherited in an autosomal dominant manner. In Finland, genetic background of HCM is unique, with a few founder mutations in cardiac sarcomere gene...
1 Citations Source Cite
Published on Sep 14, 2016in Frontiers in Physiology 3.39
Janelle Geist2
Estimated H-index: 2
(University of Maryland, Baltimore),
Aikaterini Kontrogianni-Konstantopoulos24
Estimated H-index: 24
(University of Maryland, Baltimore)
Myosin Binding Protein-C (MyBP-C) comprises a family of accessory proteins that includes the cardiac, slow skeletal, and fast skeletal isoforms. The three isoforms share structural and sequence homology, and localize at the C-zone of the sarcomeric A-band where they interact with thick and thin filaments to regulate the cycling of actomyosin crossbridges. The cardiac isoform, encoded by MYBPC3, has been extensively studied over the last several decades due to its high mutational rate in congenit...
5 Citations Source Cite