scholarly journals Identification of MYOM2 as a candidate gene in hypertrophic cardiomyopathy and Tetralogy of Fallot, and its functional evaluation in the Drosophila heart

2020 ◽  
Vol 13 (12) ◽  
pp. dmm045377
Author(s):  
Emilie Auxerre-Plantié ◽  
Tanja Nielsen ◽  
Marcel Grunert ◽  
Olga Olejniczak ◽  
Andreas Perrot ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Candidate Gene ◽  
Tetralogy Of Fallot ◽  
Heart Function ◽  
Heart Diseases ◽  
Critical Role ◽  
Disease Genes ◽  
Compound Heterozygous ◽  
Functional Evaluation ◽  
Myosin Binding

ABSTRACTThe causal genetic underpinnings of congenital heart diseases, which are often complex and multigenic, are still far from understood. Moreover, there are also predominantly monogenic heart defects, such as cardiomyopathies, with known disease genes for the majority of cases. In this study, we identified mutations in myomesin 2 (MYOM2) in patients with Tetralogy of Fallot (TOF), the most common cyanotic heart malformation, as well as in patients with hypertrophic cardiomyopathy (HCM), who do not exhibit any mutations in the known disease genes. MYOM2 is a major component of the myofibrillar M-band of the sarcomere, and a hub gene within interactions of sarcomere genes. We show that patient-derived cardiomyocytes exhibit myofibrillar disarray and reduced passive force with increasing sarcomere lengths. Moreover, our comprehensive functional analyses in the Drosophila animal model reveal that the so far uncharacterized fly gene CG14964 [herein referred to as Drosophila myomesin and myosin binding protein (dMnM)] may be an ortholog of MYOM2, as well as other myosin binding proteins. Its partial loss of function or moderate cardiac knockdown results in cardiac dilation, whereas more severely reduced function causes a constricted phenotype and an increase in sarcomere myosin protein. Moreover, compound heterozygous combinations of CG14964 and the sarcomere gene Mhc (MYH6/7) exhibited synergistic genetic interactions. In summary, our results suggest that MYOM2 not only plays a critical role in maintaining robust heart function but may also be a candidate gene for heart diseases such as HCM and TOF, as it is clearly involved in the development of the heart.This article has an associated First Person interview with Emilie Auxerre-Plantié and Tanja Nielsen, joint first authors of the paper.

scholarly journals Identification of MYOM2 as a candidate gene in hypertrophic cardiomyopathy and Tetralogy of Fallot and its functional evaluation in the Drosophila heart

2020 ◽  
Author(s):  
Emilie Auxerre-Plantié ◽  
Tanja Nielsen ◽  
Marcel Grunert ◽  
Olga Olejniczak ◽  
Andreas Perrot ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Candidate Gene ◽  
Tetralogy Of Fallot ◽  
Heart Function ◽  
Heart Diseases ◽  
Heart Defects ◽  
Critical Role ◽  
Disease Genes ◽  
Compound Heterozygous ◽  
Functional Evaluation

ABSTRACTThe causal genetic underpinnings of congenital heart diseases, which are often complex and with multigenic background, are still far from understood. Moreover, there are also predominantly monogenic heart defects, such as cardiomyopathies, with known disease genes for the majority of cases. In this study, we identified mutations in myomesin 2 (MYOM2) in patients with Tetralogy of Fallot (TOF), the most common cyanotic heart malformation, as well as in patients with hypertrophic cardiomyopathy (HCM), who do not exhibit any mutations in the known disease genes. MYOM2 is a major component of the myofibrillar M-band of the sarcomere and a hub gene within interactions of sarcomere genes. We show that patient-derived cardiomyocytes exhibit myofibrillar disarray and reduced passive force with increasing sarcomere lengths. Moreover, our comprehensive functional analyses in the Drosophila animal model reveal that the so far uncharacterized fly gene CG14964 may be an ortholog of MYOM2, as well as other myosin binding proteins (henceforth named as Drosophila Myomesin and Myosin Binding protein (dMnM)). Its partial loss-of-function or moderate cardiac knockdown results in cardiac dilation, whereas more severely reduced function causes a constricted phenotype and an increase in sarcomere myosin protein. Moreover, compound heterozygous combinations of CG14964 and the sarcomere gene Mhc (MYH6/7) exhibited synergistic genetic interactions. In summary, our results suggest that MYOM2 not only plays a critical role in maintaining robust heart function but may also be a candidate gene for heart diseases such as HCM and TOF, as it is clearly involved in the development of the heart.SUMMARY STATEMENTMYOM2 plays a critical role in establishing or maintaining robust heart function and is a candidate gene for heart diseases such as hypertrophic cardiomyopathy and Tetralogy of Fallot.

scholarly journals Myosin-binding Protein C Compound Heterozygous Variant Effect on the Phenotypic Expression of Hypertrophic Cardiomyopathy

2017 ◽  
Author(s):  
Julianny Freitas Rafael ◽  
Fernando Eugênio dos Santos Cruz Filho ◽  
Antônio Carlos Campos de Carvalho ◽  
Ilan Gottlieb ◽  
José Guilherme Cazelli ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Protein C ◽  
Binding Protein ◽  
Phenotypic Expression ◽  
Compound Heterozygous ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Heterozygous Variant ◽  
Myosin Binding ◽  
Variant Effect

Abstract 91: Pathogenicity of Naturally Produced Fragments of Cardiac Myosin Binding Protein C and Their Effects on Heart Function and Failure

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Md. Abdur Razzaque
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Protein Expression ◽  
Protein C ◽  
Heart Function ◽  
Binding Protein ◽  
Ischemia Reperfusion ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

Background: Myosin binding protein C (MyBP-C) is a thick filament protein consisting of 1274 amino acid residues (149kD) and mutations in the cardiac isoform (cardiac MyBP-C; cMyBP-C) are responsible for a substantial proportion (20-35%) of identified cases of familial hypertrophic cardiomyopathy (FHC). Recently we found a 40kD fragment is produced from cMyBP-C when the heart is stressed, using a stimulus such as ischemia reperfusion injury. This fragment can be detected in both the mouse and human heart and appears to be stable. Its ability to interfere with normal cardiac function is unexplored. Methods and Results: To understand the potential pathogenicity of the 40kd fragment in vivo, we generated cardiac myocyte-specific transgenic mice (TG) using a Tet-Off inducible system to permit controlled expression in cardiomyocytes. When 40kD protein expression is induced by crossing the responder animals with tetracycline transactivator (tTA) mice, the double TG mice show protein expression and, subsequently, sarcomere dysgenesis and altered cardiac geometry. The double transgenic heart fails between 3 to 17 weeks of age. Expression, the fragment in cardiomyocytes led to development of significant cardiac hypertrophy with myofibrillar disarray and fibrosis. Subsequent analyses showed that MEK-ERK hypertrophic signaling pathways were activated. To determine the role of this pathway in the pathogenic response being generated, we subjected an experimental cohort of animals to treatment with the MAPK/ERK kinase inhibitor U0126 during pregnancy. The drug effectively improved heart function and prolonged survival as compared to the untreated control cohort. Conclusions: The data show that a 40kD fragment of cMyBP-C, which is generated during the development of heart disease in both the mouse and human, is a pathogenic fragment whose presence leads to hypertrophic cardiomyopathy and heart failure. Blockade of the MEK-ERK pathway was effective therapeutically in decreasing morbidity and increasing lifespan in the face of continued synthesis of the fragment.

Overexpression of Pygo2 Increases Differentiation of Human Umbilical Cord Mesenchymal Stem Cells into Cardiomyocyte-like Cells

2020 ◽  
Vol 20 (4) ◽  
pp. 318-324 ◽  
Author(s):  
Lei Yang ◽  
Shuoji Zhu ◽  
Yongqing Li ◽  
Jian Zhuang ◽  
Jimei Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Umbilical Cord ◽  
Heart Function ◽  
Critical Role ◽  
Human Umbilical Cord ◽  
Stem Cell Markers ◽  
Quantitative Real Time Pcr ◽  
Qrt Pcr

Background: Our previous studies have shown that Pygo (Pygopus) in Drosophila plays a critical role in adult heart function that is likely conserved in mammals. However, its role in the differentiation of human umbilical cord mesenchymal stem cells (hUC-MSCs) into cardiomyocytes remains unknown. Objective: To investigate the role of pygo2 in the differentiation of hUC-MSCs into cardiomyocytes. Methods: Third passage hUC-MSCs were divided into two groups: a p+ group infected with the GV492-pygo2 virus and a p− group infected with the GV492 virus. After infection and 3 or 21 days of incubation, Quantitative real-time PCR (qRT-PCR) was performed to detect pluripotency markers, including OCT-4 and SOX2. Nkx2.5, Gata-4 and cTnT were detected by immunofluorescence at 7, 14 and 21 days post-infection, respectively. Expression of cardiac-related genes—including Nkx2.5, Gata-4, TNNT2, MEF2c, ISL-1, FOXH1, KDR, αMHC and α-Actin—were analyzed by qRT-PCR following transfection with the virus at one, two and three weeks. Results : After three days of incubation, there were no significant changes in the expression of the pluripotency stem cell markers OCT-4 and SOX2 in the p+ group hUC-MSCs relative to controls (OCT-4: 1.03 ± 0.096 VS 1, P > 0.05, SOX2: 1.071 ± 0.189 VS 1, P > 0.05); however, after 21 days, significant decreases were observed (OCT-4: 0.164 ± 0.098 VS 1, P < 0.01, SOX2: 0.209 ± 0.109 VS 1, P < 0.001). Seven days following incubation, expression of mesoderm specialisation markers, such as Nkx2.5, Gata-4, MEF2c and KDR, were increased; at 14 days following incubation, expression of cardiac genes, such as Nkx2.5, Gata-4, TNNT2, MEF2c, ISL-1, FOXH1, KDR, αMHC and α-Actin, were significantly upregulated in the p+ group relative to the p− group (P < 0.05). Taken together, these findings suggest that overexpression of pygo2 results in more hUCMSCs gradually differentiating into cardiomyocyte-like cells. Conclusion: We are the first to show that overexpression of pygo2 significantly enhances the expression of cardiac-genic genes, including Nkx2.5 and Gata-4, and promotes the differentiation of hUC-MSCs into cardiomyocyte-like cells.

scholarly journals Integration of transcriptomic data identifies key hallmark genes in hypertrophic cardiomyopathy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jing Xu ◽  
Xiangdong Liu ◽  
Qiming Dai
Keyword(s):  
Machine Learning ◽  
Hypertrophic Cardiomyopathy ◽  
Heart Diseases ◽  
Expression Patterns ◽  
Support Vector ◽  
Rna Seq ◽  
Ppi Network ◽  
Learning Methods ◽  
Transcriptomic Data ◽  
Machine Learning Methods

Abstract Background Hypertrophic cardiomyopathy (HCM) represents one of the most common inherited heart diseases. To identify key molecules involved in the development of HCM, gene expression patterns of the heart tissue samples in HCM patients from multiple microarray and RNA-seq platforms were investigated. Methods The significant genes were obtained through the intersection of two gene sets, corresponding to the identified differentially expressed genes (DEGs) within the microarray data and within the RNA-Seq data. Those genes were further ranked using minimum-Redundancy Maximum-Relevance feature selection algorithm. Moreover, the genes were assessed by three different machine learning methods for classification, including support vector machines, random forest and k-Nearest Neighbor. Results Outstanding results were achieved by taking exclusively the top eight genes of the ranking into consideration. Since the eight genes were identified as candidate HCM hallmark genes, the interactions between them and known HCM disease genes were explored through the protein–protein interaction (PPI) network. Most candidate HCM hallmark genes were found to have direct or indirect interactions with known HCM diseases genes in the PPI network, particularly the hub genes JAK2 and GADD45A. Conclusions This study highlights the transcriptomic data integration, in combination with machine learning methods, in providing insight into the key hallmark genes in the genetic etiology of HCM.

scholarly journals Multiple disease genes cause hypertrophic cardiomyopathy

Heart ◽  
1994 ◽  
Vol 72 (6 Suppl) ◽  
pp. S4-S9 ◽  
Author(s):  
H. Watkins
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Disease Genes

scholarly journals The role of MDCT in the assessment of cardiac and extra-cardiac vascular defects among Egyptian children with tetralogy of Fallot and its surgical implementation

2021 ◽  
Vol 52 (1) ◽  
Author(s):  
Ahmed Elshimy ◽  
Rasha Tolba Khattab ◽  
Hend Galal Eldeen Mohamed Ali Hassan
Keyword(s):  
Tetralogy Of Fallot ◽  
Heart Diseases ◽  
Preoperative Evaluation ◽  
Vena Cava ◽  
Predictive Values ◽  
Surgical Interventions ◽  
Vascular Abnormalities ◽  
Egyptian Children ◽  
Cardiac Lesions ◽  
Cyanotic Congenital Heart Diseases

Abstract Background Tetralogy of Fallot (TOF) is considered the most common form of cyanotic congenital heart diseases (CHD), accounting for about 10% of cases. It includes four main cardiac defects, in addition to various extra-cardiac anomalies. Aim This study aimed to evaluate cardiac and extra-cardiac vascular defects associated with TOF among Egyptian children, regarding frequency and types with assessment of multi-slice or multi-detector computed tomography (MDCT) role in their diagnosis. Definitely, full detection of these vascular anomalies has utmost importance when evaluating such patients particularly before surgical intervention. Methods This study included 60 pediatric patients diagnosed as TOF, who underwent MDCT examination in our institute during period of 6 months from (March to September 2020), to confirm their trans-thoracic echocardiography (TTE) findings and detect other vascular abnormalities which cannot be precisely detected with TTE before their surgical interventions. Results The incidence of different extra-cardiac vascular defects diagnosed by MDCT among our patients was 85% which was significantly higher than that detected by TTE (55%). Moreover, MDCT was superior to TTE assessment as regards its diagnostic accuracy (96.6% vs. 80%), sensitivity (98% vs. 76.9%), and specificity (88.9% vs. 85.7%), in addition to both positive and negative predictive values. The most common anomalies detected were affecting the pulmonary artery (80%), followed by aorto-pulmonary vessels (45%), then aortic artery (40%), coronary arteries (20%), and lastly vena cava connection (6.7%). Patients’ demographic characteristics and clinical presentations were also presented. Conclusion This study confirmed that many extra-cardiac vascular defects are commonly associating cardiac lesions in TOF and emphasizing the great value of MDCT in their diagnosis. Certainly, proper detection of these anomalies will help decision-making during preoperative evaluation, corrective interventions, and further management of these cases.

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