Similar Datasets
Project description:RNA sequencing of transgenic TNNT2 variant models
| PRJNA605790 | ENA
Project description:Different single mutations on the same sarcomeric gene often cause distinct cardiomyopathy phenotypes as dilated (DCM) or hypertrophic cardiomyopathy (HCM). The key factors involved in this disease divergence is unknown and could be key for disease intervention.We generated isogenic familial DCM and HCM disease-specific human embryonic stem cells (hESCs) carrying the cTnT-DK210 and -DE160 mutation, respectively. Whole transcriptomic RNA-sequencing was used to identify the key gene involved in the earliest disease divergence of cTnT-DK210 caused DCM and cTnT-DE160 caused HCM. Results provide insight into the new molecular mechanisms underlying familial dilated cardiomyopathy.
2021-10-01 | GSE154097 | GEO
Project description:Hypertrophic cardiomyopathy (HCM) is a disease, which is difficult to diagnose at an early stage and for which there is a pressing need for more effective treatment options. The purpose of this study was to compare the molecular profile of HCM to that of ISCM and DCM for identification of protein and pathway targets that could support development of better diagnostic and treatment options for HCM. A high throughput mass spectrometry workflow was applied to achieve deep quantitative coverage of left ventricular tissue from HCM, DCM, ISCM and non-heart failure control patients. HCM had a diverse proteomic profile compared to that of DCM and ISCM. Dif-ferentially expressed proteins unique to HCM were identified based on an observed fold change of ≥ 1.5 or ≤-1.5 and q-value ≤ 0.005. Candidate proteins of interest were found to be significantly associated with clinical features of HCM. The significant association between these proteins and HCM was validated in an independent dataset. This represents one of the largest and deepest proteomic datasets for myocardial tissue reported to date. The dataset highlights the diverse proteomic profile of HCM, relative to other cardiomyopathies, and reveals disease-relevant pathways and promising biomarker candidates that are uniquely associated with HCM.
2024-08-08 | PXD054266 | Pride
Project description:Hypertrophic and dilated cardiomyopathies (HCM and DCM, respectively) are inherited disorders that may be caused by mutations to the same sarcomeric protein but have completely different clinical phenotypes. The precise mechanisms by which point mutations within the same gene bring about phenotypic diversity remain unclear. Our objective has been to develop a mechanistic explanation of diverging phenotypes in two TPM1 mutations, E62Q (HCM) and E54K (DCM). Drawing on data from the literature and novel experiments with stem cell-derived cardiomyocytes expressing the TPM1 mutations of interest, we constructed computational simulations that provide plausible explanations of the distinct muscle contractility caused by each variant. In E62Q, increased calcium sensitivity and hypercontractility was explained most accurately by a reduction in effective molecular stiffness of tropomyosin and alterations in its interactions with the actin thin filament that favor the ‘closed’ regulatory state. By contrast, the E54K mutation appears to act via long-range allosteric interactions to increase the association rate of the C-terminal troponin I mobile domain to tropomyosin/actin. These mutation-linked molecular events produce diverging alterations in gene expression that can be observed in human engineered heart tissues. Modulators of myosin activity confirm our proposed mechanisms by rescuing normal contractile behavior in accordance with predictions.
2024-12-19 | GSE251993 | GEO
Project description:Cardiomyopathies are a heterogeneous group of primary diseases of the myocardium,including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), andarrhythmogenic right ventricular cardiomyopathy (ARVC), with higher morbidity andmortality. These diseases are genetically diverse and associated with rare mutations ina large number of genes, many of which overlap among the phenotypes. To betterinvestigate the genetic overlap between these three phenotypes and to identify newgenotype-phenotype correlations, we designed a custom gene panel consisting of 115genes known to be associated with cardiomyopathic phenotypes and channelopathies.A cohort of 38 unrelated patients, 16 affected by DCM, 14 by HCM and 8 by ARVC,was recruited for the study on the basis of more severe phenotypes and family historyof cardiomyopathy and/or sudden death.
| EGAS00001002506 | EGA
Project description:Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular (LV) hypertrophy and diastolic dysfunction, which leads to LV outflow tract obstruction (LVOTO) in the majority of cases. Mutations in genes encoding sarcomeric proteins cause HCM and are identified in more than half of the patients (sarcomere-mutation positive, SMP). Currently, more than 1500 HCM-causing mutations are known. Approximately 80% of mutations are located in the MYH7 and MYBPC3 genes, encoding for the thick filament proteins β-myosin heavy chain (β-MHC) and cardiac myosin-binding protein C (cMyBP-C), respectively. Less frequent are mutations in the TNNT2 and TNNI3 genes, encoding for the thin filament proteins cardiac troponin T (cTnT) and I (cTnI). Here, we applied an unbiased proteomics approach in a large number of myectomy samples from a clinically well-characterized HCM patient group to define HCM-specific derailments as well as genotype-specific changes at protein level. Our study shows that the downregulation of metabolic pathways and the upregulation of extracellular matrix proteins are the most prominent HCM-specific disease characteristics that are present in all samples independent of their genotype.
2021-01-14 | PXD012467 | Pride
Project description:A 25-base pair deletion in the cardiac myosin binding protein-C (cMyBP-C) gene (MYBPC3), proposed to skip exon 33, modifies the C10 domain (cMyBP-CΔC10mut) and is associated with hypertrophic cardiomyopathy (HCM) and heart failure, affecting approximately 100 million South Asians. However, the molecular mechanisms underlying the pathogenicity of cMyBP-CΔC10mut in vivo are unknown. To determine whether expression of cMyBP-CΔC10mut is sufficient to cause HCM and contractile dysfunction in vivo, we generated transgenic (TG) mice having cardiac-specific protein expression of cMyBP-CΔC10mut at approximately half the level of endogenous cMyBP-C. At 12 weeks of age, significant hypertrophy was observed in TG mice expressing cMyBP-CΔC10mut. Also RNA Sequencing revealed that genes related to muscle contraction and proteosome biological process are dysregulated. Similarly,to determine whether myocardial inflammation is associated with cardiac dysfunction in dilated cardiomyopathy (DCM) caused by MYBPC3 mutation, we used the well-characterized cMyBP-C(t/t) mouse model of DCM at 3months of age.RNA-seq analysis revealed the upregulation of inflammatory pathways in the DCM hearts.
2024-03-22 | GSE262253 | GEO
Project description:Background: RBM20 gene is one of the genetic predispositions for dilated cardiomyopathy (DCM). Variants in RS domain has been reported in many DCM patients, while the pathogenicity of variants within the RNA-recognition motif remains unknown. Methods and results: We detected two human patients of I536T-RBM20 variant without DCM phenotype in sudden death cohorts. We performed splicing reporter assay and generated I538T knock-in (KI) mouse model (Rbm20I538T) in order to reveal the significance of this variant. The reporter assay revealed that human I536T variant affected TTN splicing pattern compared to wild-type. In the mouse experiments, Rbm20I538T mice presented a different splicing pattern in Ttn, Ldb3, Camk2d and Ryr2. The expression of Casq1, Mybpc2 and Myot were upregulated in Rbm20I538T mice. Whereas, Rbm20I538T mice did show neither DCM nor cardiac dysfunction by histopathological examination and ultrasound echocardiography. Conclusion: I536T-RBM20 (I538T-Rbm20) variant does not cause DCM phenotype, but changes the gene splicing and expression effect. The splicing and expression changes in Ttn and Ca handling genes such as Casq1, Camk2d and Ryr2 may be contributory to sudden arrhythmogenic death.
2022-10-05 | GSE201018 | GEO
Project description:To explore the primary cause of Dilated Cardiomyopathy in heart samples from DCM-diagnosed patients who had undergone heart transplant (hDCM), we set out to identify differentially expressed genes by massively parallel sequencing of heart samples. Methods: Heart mRNA profiles from DCM-diagnosed patients who had undergone heart transplant (hDCM) were generated by deep sequencing, in triplicate, using Illumina GAIIx.
2015-01-30 | E-GEOD-65446 | biostudies-arrayexpress
Project description:Dilated cardiomyopathy (DCM) is characterized by reduced cardiac output, as well as thinning and enlargement of left ventricular chambers. These characteristics eventually lead to heart failure. Current standards of care do not target the underlying molecular mechanisms associated with genetic forms of heart failure, driving a need to develop novel therapeutics for DCM. To identify candidate therapeutics, we developed an in vitro DCM model using induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) deficient in BCL2-associated athanogene 3 (BAG3). With these BAG3-deficient iPSC-CMs, we identified cardioprotective drugs with a phenotypic screen and deep learning. Using a library of 5500 bioactive compounds and siRNA validation, we identified that inhibiting histone deacetylase 6 (HDAC6) was cardioprotective at the sarcomere level. We translated this finding to a BAG3 cardiac-knockout (BAG3cKO) mouse model of DCM, showing that inhibiting HDAC6 with two isoform-selective inhibitors (tubastatin A and a novel inhibitor TYA-018) protected heart function. In BAG3cKO and BAG3 E455K mice, HDAC6 inhibitors improved left ventricular ejection fraction and reduced left ventricular diameter at diastole and systole. We also found that HDAC6 inhibitors protected the microtubule network from mechanical damage, increased autophagic flux, decreased apoptosis, and reduced inflammation in the heart. Our results demonstrate the power of combining iPSC-CMs with phenotypic screening and deep learning to accelerate target and drug discovery, and they support the development of novel therapies that address underlying mechanisms associated with heart disease.
2021-12-31 | GSE179656 | GEO