Ontology highlight
ABSTRACT:
PROVIDER: PRJNA671288 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Truncating variants in titin can cause dilated cardiomyopathy, however, the role of missense titin variants is less clear. In humans the heterozygous titin A178D variant is associated with dilated cardiomyopathy with left ventricular non-compaction. Using CRISPR-Cas9 mediated homology-directed repair the A178D titin variant was introduced into a mouse model. Homozygous A178D mice showed features of dilated cardiomyopathy. Total RNA was extracted from the left ventricles of WT and homozygous A178D littermate control mice and RNA-sequencing performed. Different patterns of gene expression were identified in wildtype and homozygous A178D left ventricles.
2021-02-26 | GSE154504 | GEO
Project description:Aims: Pathogenic truncating variants in the largest human protein TITIN are a leading cause of dilated cardiomyopathy. Because of the size of the gene encoding TITIN, many missense variations are identified. These are difficult to evaluate in genetic testing, as even individually rare variants are common in aggregate in normal populations. While the majority will be benign, a small subset is pathogenic, but distinction is challenging. Here, we describe the generation of a mouse model to investigate the underlying disease mechanism of a previously reported TITIN A178D missense variant identified in a family with non-compaction and dilated cardiomyopathy. Methods and Results: Heterozygous and homozygous mice carrying the TITIN A178D missense variant were characterised in vivo. Heterozygous mice had no detectable phenotype at any time point observed (up to 1 year). By contrast, homozygous mice developed dilated cardiomyopathy from 3 months. Chronic adrenergic stimulation aggravated the phenotype. Targeted transcript profiling revealed induction of the fetal gene programme and hypertrophic signalling pathways in homozygous mice, and these were confirmed at the protein level. Unsupervised proteomics identified down-regulation of TELETHONIN and FOUR-AND-A-HALF LIM DOMAIN 2, as well as the up-regulation of heat shock proteins and MYELOID LEUKEMIA FACTOR 1. Loss of TELETHONIN from the cardiac Z-disc was accompanied by proteasomal degradation; however, TELETHONIN also accumulated in the cytoplasm. In parallel, a proteo-toxic response was observed in the mice. Conclusions: We have shown that the TITIN A178D missense variant is pathogenic in homozygous mice, resulting in cardiomyopathy. We also provide evidence of the disease mechanism. Because the TITIN A178D variant abolishes binding of TELETHONIN, this leads to its abnormal cytoplasmic accumulation. Subsequent degradation of TELETHONIN by the proteasome results in proteasomal overload, and activation of a proteo-toxic response. The latter appears to be a driving factor for the cardiomyopathy observed in the mouse model.
2021-03-01 | PXD020390 | Pride
Project description:MicroRNAs negatively regulate gene expression and may serve as biomarkers for human cardiomyopathy. In the domestic cat, hypertrophic cardiomyopathy (HCM) represents the most common primary cardiomyopathy. In humans, the etiology of HCM is linked to mutations in genes of contractile muscle proteins, while in cats a clear proof for causal mutations is missing. The etiology of feline HCM is uncertain. Diagnosis is made by heart ultrasound examination and measuring the serum level of N-terminal pro B-type natriuretic peptide. The purpose of this study was to investigate whether microRNA profiles in the serum of cats with HCM are different from the profiles of healthy cats and whether specific miRNAs can be detected to serve as potential biomarkers for feline HCM or may help in understanding the etiology of this disease
2015-07-22 | GSE49427 | GEO
Project description:Gene expression profiling in homozygous LMNA-/- mouse model with cardiomyopathy phenotype unraveled novel LMNA-mediated alterations of signaling pathways leading to dilated cardiomyopathy
2020-04-27 | GSE133693 | GEO
Project description:MicroRNAs negatively regulate gene expression and may serve as biomarkers for human cardiomyopathy. In the domestic cat, hypertrophic cardiomyopathy (HCM) represents the most common primary cardiomyopathy. In humans, the etiology of HCM is linked to mutations in genes of contractile muscle proteins, while in cats a clear proof for causal mutations is missing. The etiology of feline HCM is uncertain. Diagnosis is made by heart ultrasound examination and measuring the serum level of N-terminal pro B-type natriuretic peptide. The purpose of this study was to investigate whether microRNA profiles in the serum of cats with HCM are different from the profiles of healthy cats and whether specific miRNAs can be detected to serve as potential biomarkers for feline HCM or may help in understanding the etiology of this disease Blood was drawn from two groups of cats: 12 healthy cats and 11 cats suffering from hypertrophic cardiomyopathy. After clotting, samples were centrifuged and total mRNA was extracted from serum. These 23 serum samples were analyzed and the groups were compared
2015-07-22 | E-GEOD-49427 | biostudies-arrayexpress
Project description:We report the application of RNA-sequencing technology for high-throughput profiling of Drosophila that express clinical variants of feline-MyBPC3 associated with Hypertrophic Cardiomyopathy (HCM).
2020-12-04 | GSE141574 | GEO
Project description:Single RNA sequencing analysis of myosin binding protein C3 (mybpc-3) associated Hypertrophic Cardiomyopathy to identify single cell gene expression changes across common pathological mechanisms and species-specific distinctions in human, feline, and murine heart tissues.
2024-03-06 | GSE255296 | GEO
Project description:Pathogenic variants in ACTN2, coding for alpha-actinin 2, are known to be rare causes of Hyper-trophic Cardiomyopathy. However, little is known about the underlying disease mechanisms. Adult heterozygous mice carrying the Actn2 M228T variant were phenotyped by echocardiog-raphy. For homozygous mice, viable E15.5 embryonic hearts were analysed by High Resolution Episcopic Microscopy and wholemount staining, complemented by unbiased proteomics, qPCR and Western blotting. Heterozygous Actn2 M228T mice have no overt phenotype. Only mature males show molecular parameters indicative of cardiomyopathy. By contrast, the variant is em-bryonically lethal in the homozygous setting and E15.5 hearts show multiple morphological ab-normalities. Molecular analyses, including unbiased proteomics, identified quantitative abnormal-ities in sarcomeric parameters, cell cycle defects and mitochondrial dysfunction. The mutant al-pha-actinin protein is found to be destabilised, associated with increased activity of the ubiqui-tin-proteosomal system. This missense variant in alpha-actinin renders the protein less stable. In response, the ubiquitin-proteosomal system is activated; a mechanism which has been implicated in cardiomyopathies previously. In parallel, lack of functional alpha-actinin is thought to cause energetic defects through mitochondrial dysfunction. This seems, together with cell cycle defects, the likely cause of death of the embryos. The defects also have wide-ranging morphological con-sequences.
2023-05-10 | PXD039226 | Pride
Project description:Deep-intronic variants in hypertrophic cardiomyopathy
| PRJNA393768 | ENA
Project description:RNA-seq of human cells Edited using CRISPR vs parental and Unedited control. We identified a rare homozygous intronic variant in the ATP2B1 locus (rs111337717; chr12:89643729, T>C) that is associated with the severity of COVID-19 (i.e., symptomatic versus asymptomatic patients). Next, we employed CRISPR/Cas9 technology to develop the disease mutation observed in high-risk patients. Several edited single colonies were picked and expanded followed by DNA sequencing, and four clones with desired homozygous modifications were identified. The transcriptional profiles of N=4 C/C clones were compared then to those of T/T controls comprising one parental cell line and three unedited post-selection HEK293T cell clones.
2024-05-13 | E-MTAB-13916 | biostudies-arrayexpress