Skeletal muscle biopsies of patients with myotonic dystrophy (DM) and non-DM neuro-muscular disorders
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE13608 | GEO | 2017/08/29
SECONDARY ACCESSION(S): PRJNA110629
REPOSITORIES: GEO
Similar Datasets
Project description:The prevailing patho-mechanistic paradigm for myotonic dystrophy (DM) is that the aberrant presence of embryonic isoforms is responsible for many, if not most, aspects of the pleiotropic disease phenotype. In order to identify such aberrantly expressed isoforms in skeletal muscle of DM type 1 (DM1) and type 2 (DM2) patients, we utilized the Affymetrix exon array to characterize the largest collection of DM samples analyzed to date, and included non-DM dystrophic muscle samples (NMD) as disease controls.
2016-01-05 | GSE48828 | GEO
Project description:The prevailing patho-mechanistic paradigm for myotonic dystrophy (DM) is that the aberrant presence of embryonic isoforms is responsible for many, if not most, aspects of the pleiotropic disease phenotype. In order to identify such aberrantly expressed isoforms in skeletal muscle of DM type 1 (DM1) and type 2 (DM2) patients, we utilized the Affymetrix exon array to characterize the largest collection of DM samples analyzed to date, and included non-DM dystrophic muscle samples (NMD) as disease controls. For the exon array profiling on the Human Exon 1.0 ST array (Affymetrix Santa Clara, CA) we used a panel of 28 skeletal muscle biopsies from DM1 (n=8), DM2 (n=10), Becker muscular dystrophy, BMD, (n=3), Duchenne muscular dystrophy, DMD (n=1), Tibial muscular dystrophy, TMD, (n=2) and normal skeletal muscle (n=4). Normal control RNAs were purchased commercially. .CEL files were generated with a pre-commercial version of the Affymetrix processing software, and the headers might be non-standard. In our lab, users of the Partek software could use them, whereas users of GeneSpring had to modify the header information.
2016-01-05 | E-GEOD-48828 | biostudies-arrayexpress
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:For some neurological disorders, disease is primarily RNA-mediated due to expression of non-coding microsatellite expansion RNAs (RNAexp). Toxicity is thought to result from enhanced binding of proteins to these expansions and depletion from their normal cellular targets. However, experimental evidence for this sequestration model is lacking. Here, we use HITS-CLIP and pre-mRNA processing analysis of human control versus myotonic dystrophy (DM) brains to provide compelling evidence for this RNA toxicity model. MBNL2 binds directly to DM repeat expansions in the brain resulting in depletion from its normal RNA targets with downstream effects on alternative splicing and polyadenylation. Similar RNA processing defects were detected in Mbnl compound knockout mice, highlighted by dysregulation of Mapt splicing and fetal tau isoform expression in adults. These results demonstrate that MBNL proteins are directly sequestered by RNAexp in the DM brain and introduce a powerful experimental tool to evaluate RNA-mediated toxicity in other expansion diseases. HITS-CLIP analysis was performed to identify RNA binding sites of MBNL2 in control, DM type 1 (DM1), and DM type 2 (DM2) autopsy-derived brain (n=3). Two regions of the brain selected for the study included the frontal cortex and hippocampus. Libraries were sequenced and wiggle files were generated for each biological replicate as well as three pooled biological replicates (3BRs) per group (control, DM1, and DM2). In addition, differential CLIP analysis (dCLIP) was performed to normalize binding data between groups and identify statistically significant changes in binding. The dCLIP analysis generated bedgraph files representing normalized binding profiles of MBNL2 in each group (control, DM1, and DM2) for visualization and comparative analysis. PolyA-seq was performed on control, DM1, and DM2 autopsy-derived brain samples (hippocampus and frontal cortex, n=3) as well as wild-type (WT) and Mbnl1; Mbnl2 conditional double knockout (Mbnl1-/-; Mbnl2c/c; Nestin-Cre+/- or DKO) brain (n=3). Libraries were sequenced and the resultant files were processed and aligned to the reference genomes (hg19 and mm10). Further computational processing was performed to remove internal oligo(dT) mis-priming events, identify valid polyA sites, and trim to the exact polyA sites. BedGraph files were generated for each group in human (control, DM1, and DM2) and mouse (WT and Mbnl DKO) for comparative visualization.
2015-07-30 | E-GEOD-68890 | biostudies-arrayexpress
Project description:Myotonic dystrophy (dystrophia myotonica, DM) is caused by expansions of CTG (type 1; DM1) or CCTG (type 2; DM2) repeats in the non-coding regions of the DMPK and CNBP genes, and patients with DM1 or DM2 often suffer from sudden cardiac death due to lethal arrhythmia. Specific molecular changes that underlie DM cardiac pathology have been linked to repeat-associated depletion of Muscleblind-like (MBNL) 1 and 2 proteins and upregulation of CUGBP Elav-like family member 1. Aims: We aim to create an Mbnl KO mouse model recapitulating DM cardiogenic death not under anesthesia, since none of the DM mouse models have reached this goal. Besides, it is unclear whether dysfunction of cardiomyocytes, among other cell types in the heart, can solely drive phenotypes. Methods and Results: We generated Myh6-Cre DKO (Mbnl1-/-; Mbnl2cond/cond; Myh6-Cre+/-) mice that completely eliminate Mbnl1/2 expression in cardiomyocytes. In this model, we found increased myocardial fibrosis, dilated cardiomyopathy and various arrhythmias. Importantly, we observed spontaneous lethal arrhythmic events in the context of shortened lifespan. RNA sequencing (RNA-seq) revealed mis-splicing events involving sarcomeric structure, mitochondrial dynamics and vesicular trafficking that mimics DM hearts. Gene expression changes were also noted by RNA-seq, and confirmed by qPCR. Notably, immunoblotting revealed a nearly 6-fold increase of Calsequestrin 1 and 50% reduction of epidermal growth factor proteins. Conclusion: These results showed that complete elimination of MBNL1/2 in mouse cardiomyocytes is sufficient to elicit a full spectrum of DM cardiac phenotypes including cardiac-related sudden death, and therefore these mice could serve as a useful model for studying DM heart pathogenesis and related translational research.
2022-01-01 | GSE184574 | GEO
Project description:Myotonic dystrophy is caused by expanded CTG/CCTG microsatellite repeats, leading to multi-systemic symptoms in skeletal muscle, heart, gastrointestinal, endocrine, and central nervous systems (CNS), among others. For many patients, CNS issues can be as or more debilitating than muscle symptoms; they include hypersomnolence, executive dysfunction, white matter atrophy, and neurofibrillary tangles. Although transcriptomes from DM1 skeletal muscle have provided useful insights into pathomechanisms and biomarkers, similarly extensive studies have not yet been performed in the CNS. To elucidate underlying causes of CNS dysfunction in patients, we have generated and analyzed RNA-seq transcriptomes from the frontal cortex of 21 DM1 patients, 4 DM2 patients, and 8 unaffected controls. One hundred and thirty high confidence splicing changes were identified, many occurring exclusively in the CNS and not in the periphery. Mis-spliced exons were found in neurotransmitter receptors, ion channels, and synaptic scaffolds, and we identified an alternative exon in GRIP1 that modulates association with kinesins. Splicing changes exhibited a gradient of severity correlating with CTG repeat length, as measured by optical mapping of individual DNA molecules. All individuals studied, including those with modest splicing defects, showed a subset of alleles with repeats longer than 1000 CTGs. Analyses of gene expression changes showed up-regulation of genes transcribed in microglia and endothelial cells, suggesting neuroinflammation, and down-regulation of genes transcribed in neurons. Gene expression changes for RNAs encoding proteins detectable in CSF were also found to correlate with mis-splicing, with implications for CNS biomarkers of disease severity. These findings provide a framework for future mechanistic and therapeutic studies of CNS issues in DM.
2020-09-04 | GSE157428 | GEO
Project description:Myotonic Dystrophy Type-2 (DM2) is an autosomal dominant disease caused by the expansion of a CCTG tetraplet repeat. It is a multisystemic disorder, affecting skeletal muscles, the heart, the eye, the central nervous system and the endocrine system. Whole mRNAs expression was measured in the muscle of DM2 patients and compared it to controls.We identified distinct genes modulated in DM2 patients compared to controls. Our study included 10 DM2 and 10 control (CTR) muscle biopsies from biceps brachii. DM2 and CTR were age- and sex- matched. Most DM2 patients had myotonia and cataract, two disease hallmarks, while differences in other clinical parameters (muscle strenght, diabetes, CPK, FT3, FT4, TSH, ejection fraction) were not significant. Genes expression was assessed by Affymetrix Gene Chip Human Exon 1.0 ST Array.
2015-04-05 | E-GEOD-37084 | biostudies-arrayexpress
Project description:Myotonic Dystrophy Type-2 (DM2) is an autosomal dominant disease caused by the expansion of a CCTG tetraplet repeat. It is a multisystemic disorder, affecting skeletal muscles, the heart, the eye, the central nervous system and the endocrine system The expression of 365 miRNAs was measured in the muscle of DM2 patients and compared it to controls and were identified distinct miRNAs modulated in DM2 patients compared to controls. Our study included 10 DM2 and 9 control (CTR) muscle biopsies from biceps brachii. DM2 and CTR were age- and sex- matched. Most DM2 patients had myotonia and cataract, two disease hallmarks, while differences in other clinical parameters (muscle strenght, diabetes, CPK, FT3, FT4, TSH, ejection fraction) were not significant. miRNAs expression was assessed by Applied Biosystems Human TaqMan Low Density Array (TLDA, v1.0).
2012-08-27 | E-GEOD-37794 | biostudies-arrayexpress
Project description:Myotonic Dystrophy Type-2 (DM2) is an autosomal dominant disease caused by the expansion of a CCTG tetraplet repeat. It is a multisystemic disorder, affecting skeletal muscles, the heart, the eye, the central nervous system and the endocrine system. Whole mRNAs expression was measured in the muscle of DM2 patients and compared it to controls.We identified distinct genes modulated in DM2 patients compared to controls.
2015-04-05 | GSE37084 | GEO
Project description:Myotonic Dystrophy Type-2 (DM2) is an autosomal dominant disease caused by the expansion of a CCTG tetraplet repeat. It is a multisystemic disorder, affecting skeletal muscles, the heart, the eye, the central nervous system and the endocrine system The expression of 365 miRNAs was measured in the muscle of DM2 patients and compared it to controls and were identified distinct miRNAs modulated in DM2 patients compared to controls.
2012-08-27 | GSE37794 | GEO