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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 Carrier43
Estimated H-index: 43
(University of Hamburg),
Giulia Mearini16
Estimated H-index: 16
(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.
  • References (152)
  • Citations (46)
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References152
Newest
Published on Oct 1, 2015in Journal of Molecular and Cellular Cardiology 5.30
Tilo Thottakara1
Estimated H-index: 1
(University of Hamburg),
Felix W. Friedrich13
Estimated H-index: 13
(University of Hamburg)
+ 11 AuthorsJulia Münch5
Estimated H-index: 5
Abstract Background Hypertrophic cardiomyopathy (HCM) is an autosomal-dominant disease with mutations in genes encoding sarcomeric proteins. Previous findings suggest deregulation of the ubiquitin proteasome system (UPS) in HCM in humans and in a mouse model of HCM ( Mybpc3 -targeted knock-in (KI) mice). In this study we investigated transcript levels of several muscle-specific E3 ubiquitin ligases in KI mice and aimed at identifying novel protein targets. Methods and Results Out of 9 muscle-spe...
14 Citations Source Cite
Published on Jul 1, 2015in European Journal of Human Genetics 3.64
Marja W. Wessels29
Estimated H-index: 29
(Erasmus University Rotterdam),
Johanna C. Herkert12
Estimated H-index: 12
+ 7 AuthorsDennis Dooijes36
Estimated H-index: 36
(Utrecht University)
Familial hypertrophic cardiomyopathy (HCM) is usually caused by autosomal dominant pathogenic mutations in genes encoding sarcomeric or sarcomere-associated cardiac muscle proteins. The disease mainly affects adults, although young children with severe HCM have also been reported. We describe four unrelated neonates with lethal cardiomyopathy, and performed molecular studies to identify the genetic defect. We also present a literature overview of reported patients with compound heterozygous or h...
30 Citations Source Cite
Published on May 7, 2015in European Heart Journal 23.43
Jan Haas21
Estimated H-index: 21
(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...
202 Citations Source Cite
Published on May 1, 2015in Journal of Medical Genetics 5.75
Chiara Calore12
Estimated H-index: 12
(University of Padua),
Marzia De Bortoli13
Estimated H-index: 13
(University of Padua)
+ 7 AuthorsPaola Melacini26
Estimated H-index: 26
(University of Padua)
Background Mutations in the cardiac myosin binding protein C ( MYBPC3 ) gene account for a significant proportion of patients affected with hypertrophic cardiomyopathy (HCM). The aim of this study was to evaluate the penetrance and the impact of a frequent founder MYBPC3 mutation on HCM clinical expression and prognosis. Methods and results Mutation screening of MYBPC3 gene was performed in 97 HCM probands. Nineteen (19.5%) resulted to be carriers of the founder p.F305Pfs*27 mutation and other 4...
13 Citations Source Cite
Published on Apr 1, 2015in Cardiovascular Research 6.29
Iacopo Olivotto42
Estimated H-index: 42
,
Giulia d’Amati38
Estimated H-index: 38
(Sapienza University of Rome)
+ 7 AuthorsMichelle Michels29
Estimated H-index: 29
(Erasmus University Rotterdam)
Mutations in cardiac sarcomere protein genes are associated with a variety of clinical phenotypes, including hypertrophic (HCM), dilated (DCM), and restrictive (RCM) cardiomyopathy as well as left ventricular non-compaction, with the overlap of morpho-functional manifestations in individual patients and families. Over time, initial phenotypes may undergo profound changes which determine clinical course and disease progression. Although genetic defects causing HCM and DCM have opposite effects at...
31 Citations Source Cite
Published on Apr 1, 2015in Cardiovascular Research 6.29
Carolyn Y. Ho36
Estimated H-index: 36
(Brigham and Women's Hospital),
Philippe Charron41
Estimated H-index: 41
(French Institute of Health and Medical Research)
+ 3 AuthorsYigal M. Pinto65
Estimated H-index: 65
(University of Amsterdam)
Genetic studies in the 1980s and 1990s led to landmark discoveries that sarcomere mutations cause both hypertrophic and dilated cardiomyopathies. Sarcomere mutations also likely play a role in more complex phenotypes and overlap cardiomyopathies with features of hypertrophy, dilation, diastolic abnormalities, and non-compaction. Identification of the genetic cause of these important conditions provides unique opportunities to interrogate and characterize disease pathogenesis and pathophysiology,...
104 Citations Source Cite
Published on Apr 1, 2015in Cardiovascular Research 6.29
Dirk J. Duncker57
Estimated H-index: 57
(Erasmus University Medical Center),
Jeroen Bakkers36
Estimated H-index: 36
(Utrecht University)
+ 3 AuthorsLucie Carrier43
Estimated H-index: 43
(University of Hamburg)
Over the past decade, our understanding of cardiomyopathies has improved dramatically, due to improvements in screening and detection of gene defects in the human genome as well as a variety of novel animal models (mouse, zebrafish, and drosophila) and in silico computational models. These novel experimental tools have created a platform that is highly complementary to the naturally occurring cardiomyopathies in cats and dogs that had been available for some time. A fully integrative approach, w...
23 Citations Source Cite
Published on Apr 1, 2015in Cardiovascular Research 6.29
EschenhagenThomas66
Estimated H-index: 66
(University of Hamburg),
Christine L. Mummery78
Estimated H-index: 78
(Leiden University),
Björn C. Knollmann35
Estimated H-index: 35
(Vanderbilt University)
One of the obstacles to a better understanding of the pathogenesis of human cardiomyopathies has been poor availability of heart-tissue samples at early stages of disease development. This has possibly changed by the advent of patient-derived induced pluripotent stem cell (hiPSC) from which cardiomyocytes can be derived in vitro . The main promise of hiPSC technology is that by capturing the effects of thousands of individual gene variants, the phenotype of differentiated derivatives of these ce...
35 Citations Source Cite
Published on Apr 1, 2015in Cardiovascular Research 6.29
Jolanda van der Velden40
Estimated H-index: 40
(VU University Medical Center),
Carolyn Y. Ho36
Estimated H-index: 36
(Brigham and Women's Hospital)
+ 3 AuthorsLucie Carrier43
Estimated H-index: 43
(University of Hamburg)
The clinical variability in patients with sarcomeric cardiomyopathies is striking: a mutation causes cardiomyopathy in one individual, while the identical mutation is harmless in a family member. Moreover, the clinical phenotype varies ranging from asymmetric hypertrophy to severe dilatation of the heart. Identification of a single phenotype-associated disease mechanism would facilitate the design of targeted treatments for patient groups with different clinical phenotypes. However, evidence fro...
29 Citations Source Cite
Published on Feb 1, 2015in Science Advances
Michael J. Previs14
Estimated H-index: 14
(University of Vermont),
Benjamin L. Prosser17
Estimated H-index: 17
(University of Pennsylvania)
+ 7 AuthorsDavid M. Warshaw12
Estimated H-index: 12
(University of Vermont)
The beating heart exhibits remarkable contractile fidelity over a lifetime, which reflects the tight coupling of electrical, chemical, and mechanical elements within the sarcomere, the elementary contractile unit. On a beat-to-beat basis, calcium is released from the ends of the sarcomere and must diffuse toward the sarcomere center to fully activate the myosin- and actin-based contractile proteins. The resultant spatial and temporal gradient in free calcium across the sarcomere should lead to n...
33 Citations Source Cite
Cited By46
Newest
Published on Apr 11, 2019in Scientific Reports 4.12
Mika Tarkiainen2
Estimated H-index: 2
,
Petri Sipola13
Estimated H-index: 13
+ 6 AuthorsJohanna Kuusisto80
Estimated H-index: 80
(University of Eastern Finland)
This manuscript has not been published before and is not currently being considered for publication elsewhere. Increased septal convexity of left ventricle has been described in subjects with hypertrophic cardiomyopathy (HCM) -causing mutations without left ventricular hypertrophy (LVH). Our objective was to study septal convexity by cardiac magnetic resonance (CMR) in subjects with the Finnish founder mutation Q1016X in the myosin-binding protein C gene (MYBPC3). Septal convexity was measured i...
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Published on May 3, 2019in Cardiovascular Research 6.29
Diederik W.D. Kuster9
Estimated H-index: 9
(Loyola University Chicago),
Thomas L. Lynch5
Estimated H-index: 5
(Loyola University Chicago)
+ 7 AuthorsSakthivel Sadayappan27
Estimated H-index: 27
(Loyola University Chicago)
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Published on May 1, 2019in Pflügers Archiv: European Journal of Physiology 2.77
Maksymilian Prondzynski6
Estimated H-index: 6
(University of Hamburg),
Giulia Mearini16
Estimated H-index: 16
(University of Hamburg),
Lucie Carrier43
Estimated H-index: 43
(University of Hamburg)
Hypertrophic cardiomyopathy (HCM) is an inherited myocardial disease with an estimated prevalence of 1:200 caused by mutations in sarcomeric proteins. It is associated with hypertrophy of the left ventricle, increased interstitial fibrosis, and diastolic dysfunction for heterozygous mutation carriers. Carriers of double heterozygous, compound heterozygous, and homozygous mutations often display more severe forms of cardiomyopathies, ultimately leading to premature death. So far, there is no cura...
1 Citations Source Cite
Published on May 1, 2019in bioRxiv
Alexandra Dainis2
Estimated H-index: 2
(Stanford University),
Elizabeth Tseng9
Estimated H-index: 9
(Pacific Biosciences)
+ 3 AuthorsEuan A. Ashley55
Estimated H-index: 55
(Stanford University)
Background: Clinical sequencing has traditionally focused on genomic DNA through the use of targeted panels and exome sequencing, rather than investigating the potential transcriptomic consequences of disease-associated variants. RNA sequencing has recently been shown to be an effective additional tool for identifying disease-causing variants. We here use targeted long-read genome and transcriptome sequencing to efficiently and economically identify molecular consequences of a rare, disease-asso...
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Published on Apr 24, 2019in Human Mutation 5.36
Konstantinos Kolokotronis , Jirko Kühnisch (Max Delbrück Center for Molecular Medicine)+ 8 AuthorsSabine Klaassen (Humboldt University of Berlin)
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Published on Apr 1, 2019in Cardiovascular Drugs and Therapy 2.77
Thomas Kaier6
Estimated H-index: 6
(St Thomas' Hospital),
Bashir Alaour1
Estimated H-index: 1
(King's College London),
Michael Marber50
Estimated H-index: 50
Chest pain is responsible for 6–10% of all presentations to acute healthcare providers. Triage is inherently difficult and heavily reliant on the quantification of cardiac Troponin (cTn), as a minority of patients with an ultimate diagnosis of acute myocardial infarction (AMI) present with clear diagnostic features such as ST-elevation on the electrocardiogram. Owing to slow release and disappearance of cTn, many patients require repeat blood testing or present with stable but elevated concentra...
1 Citations Source Cite
Published on Apr 1, 2019in Archives of Biochemistry and Biophysics 3.12
Helena M. Viola15
Estimated H-index: 15
(University of Western Australia),
Livia C. Hool23
Estimated H-index: 23
(Victor Chang Cardiac Research Institute)
Abstract Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder, characterised by myocyte remodeling, disorganisation of sarcomeric proteins, impaired energy metabolism and altered cardiac contractility. Gene mutations encoding cardiac contractile proteins account for 60% of HCM aetiology. Current drug therapy including L-type calcium channel antagonists, are used to manage symptoms in patients with overt HCM, but no treatment exists that can reverse or prevent the cardiomyopathy. De...
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Published on Mar 1, 2019in Biochimica et Biophysica Acta 3.44
Antonia T.L. Zech1
Estimated H-index: 1
,
Sonia R. Singh2
Estimated H-index: 2
(Cincinnati Children's Hospital Medical Center)
+ 1 AuthorsLucie Carrier43
Estimated H-index: 43
Abstract Autophagy (greek auto: self; phagein: eating) is a highly conserved process within eukaryotes that degrades long-lived proteins and organelles within lysosomes. Its accurate and constant operation in basal conditions ensures cellular homeostasis by degrading damaged cellular components and thereby acting not only as a quality control but as well as an energy supplier. An increasing body of evidence indicates a major role of autophagy in the regulation of cardiac homeostasis and function...
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Published on Mar 1, 2019in Netherlands Heart Journal 1.48
H.G. van Velzen1
Estimated H-index: 1
(Erasmus University Rotterdam),
Arend F.L. Schinkel36
Estimated H-index: 36
(Erasmus University Rotterdam)
+ 4 AuthorsMichelle Michels29
Estimated H-index: 29
(Erasmus University Rotterdam)
Background Previous studies have reported that global longitudinal strain (GLS) is reduced in patients with hypertrophic cardiomyopathy (HCM) while left ventricular ejection fraction (LVEF) is normal. Our aim was to assess GLS in individuals with HCM mutations without hypertrophic changes and to determine its prognostic value for the development of HCM.
1 Citations Source Cite