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Base editing effectively prevents the early-onset hypertrophic cardiomyopathy in Mybpc3 mutant mice

ABSTRACT: Base editing effectively prevents the early-onset hypertrophic cardiomyopathy in Mybpc3 mutant mice

PROVIDER: PRJNA1001311 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25491386_1.fastq.gz	Fastqsanger.gz
	SRR25491386_2.fastq.gz	Fastqsanger.gz
	SRR25491387_1.fastq.gz	Fastqsanger.gz
	SRR25491387_2.fastq.gz	Fastqsanger.gz
	SRR25491388_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Base editing effectively prevents the early-onset hypertrophic cardiomyopathy in Mybpc3 mutant mice

Project description:Pathogenic variants in MYBPC3 (myosin-binding protein C3) are the leading cause of genetic hypertrophic cardiomyopathy (HCM). Currently, there is no specific and effective treatment for this disease. Base editing is an emerging modality for treating monogenic diseases; however, its effect on MYBPC3 cardiomyopathy remains unexplored. Mybpc3-R946X/R946X mice developed early-onset left ventricular hypertrophy, systolic dysfunction, ventricular dilatation, and arrythmias. SpRY-ABEmax inefficiently corrected the Mybpc3-R946X mutation. In contrast, SpRY-ABE8e increased the efficiency by 3.6-fold and retained low level off-target editing. In vivo administration of SpRY-ABE8e efficiently corrected Mybpc3-R946X mutation in cardiomyocytes and prevented heart function decline, hypertrophic cardiomyopathy, and ventricular dysfunction. The therapeutic efficacy of SpRY-ABE8e-mediated gene correction surmounted AAV-mediated Mybpc3 gene replacement.Our study unveiled the immense potential of base editing to treat fatal inherited cardiomyopathies and opened a new avenue for the therapeutic managements of inherited cardiac diseases.

2024-04-04 | GSE239872 | GEO

Transcriptome analysis of patient derived induced pluripotent stem cell derived cardiomyocytes with severe, early onset hypertrophic cardiomyopathy due to biallelic MYBPC3 variants c.442G>A and c.506-1G>A

Project description:Induced pluripotent stem cells (iPSCs) were generated from a patient with severe, early onset hypertrophic cardiomyopathy due to pathogenic (c.506-1G>A) and low penetrance pathogenic (c.442G>A) variants in MYBPC3 in trans (i.e. MYBPC3 biallelic patient). Healthy control (WTC11, Coriell repository) iPSCs were used as reference. iPSCs were differentiated into cardiomyocytes for transcriptome analysis and assessment of the c.442G>A variant on MYBPC3 splicing.

2024-08-11 | GSE274124 | GEO

Cardiac Organoids for Modeling Hypertrophic Cardiomyopathy

Project description:BACKGROUND: MYBPC3 is one of the most mutated gene known to cause hypertrophic cardiomyopathy (HCM). However, the molecular mechanisms of how mutations in MYBPC3 lead to the onset and progression of HCM are poorly understood. Thus, advancing in-vitro studies to define these mechanisms of mutations leading to HCM are still warranted. Thus, the primary objective of this study was to investigate the molecular mechanisms underlying the pathogenesis of HCM associated with MYBPC3 mutation utilizing isogenic human-induced pluripotent stem cell (hiPSC)-derived cardiac organoids (hCOs).

2025-01-28 | GSE262876 | GEO

Heat Shock Proteins and Small Nucleolar RNAs are Dysregulated in a Drosophila Model for Feline Hypertrophic Cardiomyopathy

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

Western diet triggers cardiac dysfunction in heterozygous Mybpc3-targeted knock-in hypertrophic cardiomyopathy mice

Project description:The study investigates the effect of a heterozygous MYBPC3 mutation combined with Western diet feeding on protein expression in a HCM mouse model. Hypertrophic cardiomyopathy (HCM) is the most common inherited genetic heart disease, characterized by asymmetric left ventricular hypertrophy and diastolic dysfunction. It is generally accepted that HCM is caused by mutations in genes encoding sarcomere proteins (e.g. MYBPC3, MYH7). However, not all mutation carriers will develop HCM and, moreover, phenotypical variation in terms of clinical presentation is large. The phenotypical expression of HCM thus requires additional disease modifiers on top of a sarcomere gene mutation. Clinical reports identify obesity and related comorbidities (diabetes, hyperlipidemia, hypertension) as a major factor contributing to disease expression and severity. We aimed to mimic this situation in a HCM mouse model by feeding a Western diet (8 weeks) to mice carrying a heterozygous mutation in MYBPC3. These heterozygous mice are phenotype negative under normal conditions, but developed cardiac dysfunction and hypertrophy upon Western diet feeding. The main goal of this proteomic screening is to identify clusters of proteins and pathways that are down/upregulated specifically in the left ventricle of mice suffering from a mutation and Western diet feeding. Also, we are interested in protein expression differences caused solely by mutation or Western diet. Group 1 are Wild type mice that received normal chow; group 2 are heterozygous mice that received normal chow; group 3 are Wild type mice that received a Western diet; group 4 are heterozygous mice that received a Western diet.

2023-10-01 | PXD043345 | Pride

Analysis of microRNA expression profiles and prediction of target gene signaling pathways in familial hypertrophic cardiomyopathy with myosin-binding protein C3 (MYBPC3) gene mutations

Project description:We investigated the role of microRNA (miRNAs) in familial hypertrophic cardiomyopathy (FHCM) with MYBPC3 gene mutations. We investigated the miRNAs expression profile in three patients with FHCM with MYBPC3 gene mutations and compared the miRNA expression profiles with those of the normal control group by miRNA-seq. The significantly differentially expressed miRNAs was verified by real-time polymerase chain reaction (PCR). Target genes and signaling pathways of the identified differentially expressed miRNAs were predicted by bioinformatics analysis. The three probands were all hypertrophic obstructive cardiomyopathy with severe myocardial hypertrophy, and two of the families had a family history of sudden cardiac death, representing a “malignant” phenotype. A total of 33 significantly differentially expressed miRNAs were detected in the peripheral blood of the three probands, of which 28 were upregulated and 5 were downregulated. Real-time PCR confirmed that the expression of miR-208b-3p was consistent with the microarray results, and the difference was statistically significant (P＜0.05). Bioinformatics analysis showed that miR-208b-3p was mainly enriched in 79 target genes including Dally, Frizzled, Dvl, Nlk, Stbm and CaMKII, and gene ontology (GO) analysis of target genes showed that miR-208b was mainly involved in the processes of growth cone, phosphoprotein phosphatase activity, and postsynapse organization. Kyoto encyclopedia of genes and genomes (KEGG) analysis revealed that the target genes regulated by miR-208b-3p were mainly involved in Wnt signaling pathway. These findings show the existence of a specific expression profile of miRNAs in patients with FHCM with MYBPC3 gene mutations, in which miR-208b-3p is significantly elevated, and is implicated as a regulator of cardiac hypertrophy. In addition, our results indicate that miRNA-208b-3p activates the Wnt signaling pathway through its target gene to promote cardiac hypertrophy.

2021-05-08 | GSE150078 | GEO

RNA-sequencing of patients with hypertrophic cardiomyopathy or patients with aortic stenosis compared to heart healthy donors

Project description:Hypertrophic cardiomyopathy (HCM) is often associated with heterozygous mutations in sarcomeric genes. One of the most commonly affected genes encodes for myosin binding protein C (cMyBP-C, MYBPC3). Interestingly, most mutations in MYBPC3 lead to premature termination codons which could result in truncated fragments of cMyBP-C. However, truncated cMyBP-C has not been detect, but rather a reduction of total wildtype cMyBP-C. Nonsense mediated mRNA decay of mutated MYBPC3-mRNA was often hypothesized as cause for the reduced MYBPC3-expression, however it has not been shown in human patients. Therefore, we performed RNA-sequencing of MYBPC3trunc patients, AS-patients and donors, to detect if expression of regulatory proteins of the NMD is altered in the MYBPC3trunc patients. By gene set enrichment analysis (GSEA) of the presented data, we found expression of NMD components to be enriched in the MYBPC3trunc patients, which was furthermore associated with upregulation of UP-frameshift protein (UPF3B, UPF3B) which is a regulator of NMD.

2023-10-16 | GSE230585 | GEO

Human Hypertrophic Cardiomyopathy mRNA Profiling.

Project description:Cardiac biopsies were obtained from hypertrophic cardiomyopathy (HCM) patients and controls and subjected to mRNA profiling.

2024-11-12 | GSE249925 | GEO

Human Hypertrophic Cardiomyopathy mRNA Profiling.

Project description:Human Hypertrophic Cardiomyopathy mRNA Profiling.

| PRJNA1051135 | ENA

Human Cardiac Proteome of Hypertrophic Cardiomyopathy

Project description:This study utilized TMT to characterize the cardiac proteomic differences between patients with hypertrophic cardiomyopathy and controls.

2023-04-28 | MSV000091821 | MassIVE

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