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Series GSE157428 Query DataSets for GSE157428
Status Public on Sep 04, 2020
Title Transcriptome Alterations in Myotonic Dystrophy Frontal Cortex
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary 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.
Overall design We used Illumina RNA-sequencing across a cohort of frozen post-mortem autopsy tissue across 33 individuals to do comparative analysis.
Contributor(s) Otero BA, Poukalov K, Hildebrandt RP, Thornton CA, Jinnai K, Fujimara H, Kimura T, Hagerman KA, Sampson JB, Day JW, Wang ET
Citation(s) 33472074
Submission date Sep 03, 2020
Last update date Sep 01, 2021
Contact name Eric T Wang
Phone 3522737601
Organization name University of Florida
Department Molecular Genetics and Microbiology
Lab Wang Lab
Street address 2033 Mowry Road
City Gainesville
State/province Florida
ZIP/Postal code 32610
Country USA
Platforms (1)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
Samples (33)
GSM4764739 DM1_1
GSM4764740 DM1_2
GSM4764741 DM1_3
BioProject PRJNA661286
SRA SRP279982

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SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE157428_DM1expression_TS5.txt.gz 3.0 Mb (ftp)(http) TXT
GSE157428_DM1psitable_TS2.txt.gz 4.2 Mb (ftp)(http) TXT
GSE157428_DM2expression_TS6.txt.gz 1.4 Mb (ftp)(http) TXT
GSE157428_DM2psitable_TS4.txt.gz 3.0 Mb (ftp)(http) TXT
GSE157428_Supplemental_TS1.txt.gz 1.1 Kb (ftp)(http) TXT
GSE157428_Supplemental_TS3.txt.gz 8.7 Kb (ftp)(http) TXT
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Processed data are available on Series record

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