DM1
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB46413 | ENA |
REPOSITORIES: ENA
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Project description:Myotonic dystrophy type 1 (DM1) is a multisystem genetic disorder involving the muscle, heart, and central nervous system (CNS). The pathogenesis of CNS symptoms prevalent in patients with DM1 remains unelucidated. To elucidate the CNS pathogenesis in DM1, we investigated cell type-specific abnormalities in cortical neurons, white matter glial cells, and spinal motor neurons of patients with DM1 via laser-capture microdissection(LCM).
2022-07-07 | GSE198321 | GEO
Project description:Introduction: Myotonic dystrophy of type 1 (DM1), the most common dystrophy in adults, is an autosomal dominant inherited disease, affecting around 1 in 8000 person. Patients suffering from DM1 develop essentially muscle disorders such as myotonia, muscle weakness, muscle loss and atrophy. The disease is caused by the mutation of the DMPK "Dystrophia Myotonica Protein Kinase" gene. The mutation correspond to an abnormally large expansion of CTG tri-nucleotides repeats located in the 3'-untranslated region of this gene. Expanded CTG repeats are normally transcribed, but accumulates in RNA aggregates that sequester RNA-binding proteins such as the splicing regulator MBNL1. Consequently, due to MBNL1 sequestration, DM1 is characterized by aberrant splicing of a wide number of mRNA, which are themselves responsible for the symptoms observed in the disease. Purpose: To determine as much as possible novel splicing misregulations taking place in DM1 skeletal muscle, we performed a paired-end RNA sequencing (RNA-seq) using muscles samples of normal individuals (CTRL, n=3) versus muscles of DM1 patients (DM1, n=3). The data was analyzed by a bioinformatical software, called MISO, in order to map the alternative splicing changes between normal and DM1 muscle. The aim of this study was to get a broad and precise view of the splicing changes occurring in DM1 muscle.
2017-08-24 | GSE85984 | GEO
Project description:Myotonic dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy caused by expansion of a CTG repeat microsatellite within DMPK. In 10-20% of individuals with DM1, symptomatic onset begins at birth; these patients are classified as congenital myotonic dystrophy (CDM). While dysregulation of RNA metabolism, specifically alternative splicing, has been linked to disease pathology in adult-onset DM1, little is known about the mechanism of CDM. Biopsies from individuals (CDM), age range 0.04-16 years, were subjected to total RNA-seq to quantify the transcriptomic dysregulation throughout pediatric development. To achieve this, they were compared against age matched pediatric controls which revealed a triphasic pattern of dysregulation not before seen observed in CDM. CDM samples were also compared to adult-onset (DM1) individuals which showcased a shared disease signature to seen in all individuals with myotonic dystrophy irrespective of disease age of onset.
2022-11-17 | GSE201255 | GEO
Project description:RNA-seq of skeletal muscle model for myotonic dystrophy type 1 (DM1)
| PRJNA753820 | ENA
Project description:Myotonic dystrophy type 1 (DM1) is a dominantly inherited disease that affects multiple organ systems. Cardiac dysfunction is the second leading cause of death in DM1. We quantified gene expression in heart tissue from a heart-specific DM1 mouse model (EpA960/MCM) which inducibly expresses human DMPK exon 15 containing 960 CUG expanded repeats and that reproduced Celf1 up regulation. To assess if, in addition to splicing and miRNA defects, CUGexp RNA also perturbed the steady state mRNA levels of genes, we carried out a microarray study on wildtype E14, adult, MCM controls and DM1 mouse hearts. As anticipated we noted a large number of genes to be developmentally regulated in wildtype hearts, however, within 72h of induction of CUGexp RNA there appeared to be a coordinate adult-to-embryonic shift in steady state levels of many genes. We identified transcripts over-expressed or under-expressed in hearts of wildtype adult mice, wildtype embryonic day 14 (E14), and DM1 mice induced to express CUGexp RNA for 72h and 1wk, when compared to MCM controls. Multiple group comparison.
2014-01-24 | E-GEOD-48991 | biostudies-arrayexpress
Project description:Myotonic dystrophy type 1 (DM1) is a dominantly inherited disease that affects multiple organ systems. Cardiac dysfunction is the second leading cause of death in DM1. We quantified gene expression in heart tissue from a heart-specific DM1 mouse model (EpA960/MCM) which inducibly expresses human DMPK exon 15 containing 960 CUG expanded repeats and that reproduced Celf1 up regulation. To assess if, in addition to splicing and miRNA defects, CUGexp RNA also perturbed the steady state mRNA levels of genes, we carried out a microarray study on wildtype E14, adult, MCM controls and DM1 mouse hearts. As anticipated we noted a large number of genes to be developmentally regulated in wildtype hearts, however, within 72h of induction of CUGexp RNA there appeared to be a coordinate adult-to-embryonic shift in steady state levels of many genes.
2014-01-24 | GSE48991 | GEO
Project description:Myotonic dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy and is caused by an repeat expansion [r(CUG)exp] located in the 3' untranslated region of the DMPK gene. Symptoms include skeletal and cardiac muscle dysfunction and fibrosis. In DM1, there is a lack of established biomarkers in routine clinical practice. Thus, we aimed to identify a blood biomarker with relevance for DM1-pathophysiology and clinical presentation.
2023-05-02 | PXD024107 | Pride
Project description:In this Study, we used RNA-targeting Cas9 (RCas9) to reverse characteristic Myotonic Dystrophy (DM1) cellular phenotypes such as elimination of RNA foci, MBNL relocalization, and reversal of transcriptome-wide splicing in a mouse model of myotonic Dystrophy (DM1). Furthermore we show that gene expression is not altered with RCas9 treatment in WT mice with or without treatment with immunosuppression
2020-07-01 | GSE152033 | GEO
Project description:Myotonic dystrophy (DM) is the most common autosomal dominant muscular dystrophy and encompasses both skeletal muscle and cardiac complications. Myotonic dystrophy is nucleotide repeat expansion disorder in which type 1 (DM1) is due to a trinucleotide repeat expansion on chromosome 19 and type 2 (DM2) arises from a tetranucleotide repeat expansion on chromosome 3. Developing representative models of myotonic dystrophy in animals has been challenging due to instability of nucleotide repeat expansions, especially for DM2 which is characterized by nucleotide repeat expansions often greater than 5000 copies. To investigate mechanisms of human DM, we generated cellular models of DM1 and DM2. We used regulated MyoD expression to reprogram urine-derived cells into myotubes. In this cell model, we found impaired dystrophin expression, MBNL foci, and aberrant splicing in DM1 but not in DM2 cells. We generated induced pluripotent stem cells (iPSC) from healthy controls, DM1 and DM2 subjects and differentiated these into cardiomyocytes. DM1 and DM2 cells displayed an increase in RNA foci concomitant with cellular differentiation. IPSC-derived cardiomyocytes from DM1 but not DM2 had aberrant splicing and MBNL sequestration. High resolution imaging revealed tight association between MBNL clusters and RNA FISH foci in DM1. Ca2+ transients differed between DM1 and DM2 IPSC-derived cardiomyocytes and from healthy control cells. RNA-sequencing from DM1 and DM2 iPSC-derived cardiomyocytes both altered gene expression as well as distinct splicing patterns as differential between DM1 and DM2. Together these data support that DM1 and DM2, despite some shared clinical and molecular features, have distinct pathological signatures.
2019-02-12 | GSE125638 | GEO
Project description:Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a non-coding CTG repeat expansion in the DMPK gene. This mutation generates a toxic CUG RNA that interferes with the RNA processing of target genes in multiple tissues. Despite debilitating neurological impairment, the pathophysiological cascade of molecular and cellular events in the central nervous system has been less extensively characterized than the molecular pathogenesis of muscle/cardiac dysfunction. Particularly, the contribution of different cell types to DM1 brain disease is not clearly understood. We first used transcriptomics to compare the impact of expanded CUG RNA on the transcriptome of primary neurons, astrocytes and oligodendrocytes derived from DMSXL mice, a transgenic model of DM1. RNA sequencing revealed more frequent expression and splicing changes in glia than neuronal cells. In particular, primary DMSXL oligodendrocytes showed the highest number of transcripts differentially expressed, while DMSXL astrocytes displayed the most severe splicing dysregulation. Interestingly, the expression and splicing defects of DMSXL glia recreated molecular signatures suggestive of impaired cell differentiation: while DMSXL oligodendrocytes failed to upregulate a subset of genes that are naturally activated during the oligodendroglia differentiation, a significant proportion of missplicing events in DMSXL oligodendrocytes and astrocytes increased the expression of RNA isoforms typical of precursor cell stages. Together these data suggest that expanded CUG RNA in glial cells affects preferentially differentiation-regulated molecular events. This hypothesis was corroborated by gene ontology (GO) analyses, which revealed an enrichment for biological processes and cellular components with critical roles during cell differentiation. Finally, we combined exon ontology with phosphoproteomics and cell imaging to explore the functional impact of CUG-associated spliceopathy on downstream protein metabolism. Changes in phosphorylation, protein isoform expression and intracellular localization in DMSXL astrocytes demonstrate the far-reaching impact of the DM1 repeat expansion on cell metabolism. Our multi-omics approaches provide insight into the mechanisms of CUG RNA toxicity in the CNS with cell type resolution, and support the priority for future research on non-neuronal mechanisms and proteomic changes in DM1 brain disease.
2021-03-26 | PXD025011 | Pride