Illumina HiSeqX whole genome sequence data on 58 samples including 54 with known HTT triplet repeat expansions (2 premutation and 52 full expansions)
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PROVIDER: EGAS00001002593 | EGA |
REPOSITORIES: EGA
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Project description:Whole genome sequence (WGS) data was generated on 120 Coriell samples with the following validated repeat expansions: Fragile X Syndrome, Huntington disease, Friedreich’s ataxia, Amyotrophic Lateral Sclerosis, Myotonic Dystrophy, Spinocerebellar Ataxia 1/3 and Dentatorubral-Pallidoluysian Atrophy. These samples were sequenced using 2x150bp reads on an Illumina HiSeqX sequencer and the repeat expansions were called using ExpansionHunter to demonstrate the ability to call large repeats from high throughput, PCR-free WGS data.
| EGAS00001002462 | EGA
Project description:Huntingtons disease (HD) is a devastating neurodegenerative disease, with out effective treatment. Despite significant advances, our understanding of how an expanded CAG repeat in the amino terminus of the large ubiquitously expressed HD gene product remains incomplete. Augmented adult neurogenesis in response to acute and chronic injury, including Huntingtons disease, has been demonstrated, but its role development, disease, and recovery is largely unknown, as are the factors controlling it. The HD gene product, huntingtin (htt) is know to interact with a number of transcription factors which subsequently influence gene expression. Understanding the factors involved in controlling neurogenesis in response to disease would bridge a significant knowledge gap and have tremendous therapeutic potential. We propose to identify transcripts responsible for CAG repeat facilitated neurogenesis. Our hypothesis is that expanded CAG repeats in the Huntingtons disease gene facilitates neurogenesis by altering transcription of genes critical in neurogenesis. We have developed a model in which mouse embryonic stem cells (ESC) with expanded CAG repeats have facilitated neurogenesis. In this model more ESC with expanded CAG repeats transition to neuronal precursors and then develop into mature neurons more rapidly than control ESC. We propose to compare the gene expression profiles between ESC with expanded CAG repeats and control ESCs on days 4 and 6 of neuronal differentiation. Initial studies indicate that key transcriptional differences are occurring at these time points. Control ECS and a an ESC line with150 CAG repeats will be differentiated in triplicate, and RNA isolated form each replicate. It is anticipated that comparison of gene expression between the control and CAG repeat lines at each time point will identify transcripts involved in CAG repeat facilitated neurogenesis. Observed differences at day 4 may be more relevant to the transition from ESC to neuronal precursor whereas differences at day 6 may be more relevant to the neuronal precursor to neuron transition. Keywords: time-course
2007-12-04 | GSE9760 | GEO
Project description:Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late onset, recessively inherited neurodegenerative disorder caused by a biallelic, non-reference pentameric CCCTT(AAGGG) repeat expansion within the second intron of replication factor complex subunit 1 (RFC1). While rare compound heterozygous CANVAS cases harbor RFC1 loss-of-function mutations alongside monoallelic repeat-expansions, RFC1 expression is maintained at normal levels in the presence of biallelic expanded repeats. To investigate how these pentameric repeats cause disease, we generated CANVAS patient iPSC derived neurons and utilized calcium imaging and transcriptomic analysis to define repeat elicited gain-of-function and loss-of-function contributions to neuronal toxicity. AAGGG repeat expansions do not alter neuronal RFC1 splicing, expression, or DNA repair pathway functions. In reporter assays, AAGGG repeats are translated into pentapeptide repeat proteins that selectively accumulate in patient brains. However, neither these proteins nor repeat RNA foci were detected in iNeurons and overexpression of these repeats in isolation did not induce neuronal toxicity. CANVAS iNeurons exhibit defects in neuronal development and diminished synaptic connectivity that is rescued by CRISPR deletion of a single expanded allele. Importantly, these deficits were not replicated by knockdown of RFC1 in control neurons and showed incomplete or no rescue upon over-expression of RFC1. These findings support a repeat-dependent and RFC1-independent mechanism as the underlying cause of neurodegeneration in CANVAS, with important implications for therapeutic development in this currently untreatable condition.
2024-09-01 | GSE248344 | GEO
Project description:Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late onset, recessively inherited neurodegenerative disorder caused by a biallelic, non-reference pentameric CCCTT(AAGGG) repeat expansion within the second intron of replication factor complex subunit 1 (RFC1). While rare compound heterozygous CANVAS cases harbor RFC1 loss-of-function mutations alongside monoallelic repeat-expansions, RFC1 expression is maintained at normal levels in the presence of biallelic expanded repeats. To investigate how these pentameric repeats cause disease, we generated CANVAS patient iPSC derived neurons and utilized calcium imaging and transcriptomic analysis to define repeat elicited gain-of-function and loss-of-function contributions to neuronal toxicity. AAGGG repeat expansions do not alter neuronal RFC1 splicing, expression, or DNA repair pathway functions. In reporter assays, AAGGG repeats are translated into pentapeptide repeat proteins that selectively accumulate in patient brains. However, neither these proteins nor repeat RNA foci were detected in iNeurons and overexpression of these repeats in isolation did not induce neuronal toxicity. CANVAS iNeurons exhibit defects in neuronal development and diminished synaptic connectivity that is rescued by CRISPR deletion of a single expanded allele. Importantly, these deficits were not replicated by knockdown of RFC1 in control neurons and showed incomplete or no rescue upon over-expression of RFC1. These findings support a repeat-dependent and RFC1-independent mechanism as the underlying cause of neurodegeneration in CANVAS, with important implications for therapeutic development in this currently untreatable condition.
2024-09-01 | GSE248343 | GEO
Project description:Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late onset, recessively inherited neurodegenerative disorder caused by a biallelic, non-reference pentameric CCCTT(AAGGG) repeat expansion within the second intron of replication factor complex subunit 1 (RFC1). While rare compound heterozygous CANVAS cases harbor RFC1 loss-of-function mutations alongside monoallelic repeat-expansions, RFC1 expression is maintained at normal levels in the presence of biallelic expanded repeats. To investigate how these pentameric repeats cause disease, we generated CANVAS patient iPSC derived neurons and utilized calcium imaging and transcriptomic analysis to define repeat elicited gain-of-function and loss-of-function contributions to neuronal toxicity. AAGGG repeat expansions do not alter neuronal RFC1 splicing, expression, or DNA repair pathway functions. In reporter assays, AAGGG repeats are translated into pentapeptide repeat proteins that selectively accumulate in patient brains. However, neither these proteins nor repeat RNA foci were detected in iNeurons and overexpression of these repeats in isolation did not induce neuronal toxicity. CANVAS iNeurons exhibit defects in neuronal development and diminished synaptic connectivity that is rescued by CRISPR deletion of a single expanded allele. Importantly, these deficits were not replicated by knockdown of RFC1 in control neurons and showed incomplete or no rescue upon over-expression of RFC1. These findings support a repeat-dependent and RFC1-independent mechanism as the underlying cause of neurodegeneration in CANVAS, with important implications for therapeutic development in this currently untreatable condition.
2024-09-01 | GSE248342 | GEO
Project description:Expanded CAG/CTG repeats underlie thirteen neurological disorders, including myotonic dystrophy type 1 (DM1) and Huntington’s disease (HD). Upon expansion, CAG/CTG repeat loci acquire heterochromatic characteristics. This observation raises the hypothesis that repeat expansion provokes changes to higher-order chromatin conformation and thereby affects both gene expression in cis and the genetic instability of the repeat tract. Here we tested this hypothesis directly by performing 4C sequencing at the DMPK and HTT loci from DM1 and HD patient-derived cells. Surprisingly, chromatin contacts remain unchanged upon repeat expansion at both loci. This was true for expanded alleles with different DNA methylation levels and CTCF binding. Repeat tract sizes ranging from 15 to 1,700 repeats displayed strikingly similar chromatin interaction profiles. Moreover, the ectopic insertion of an expanded CAG repeat tract did not change the three-dimensional chromatin conformation of the surrounding genomic region. Our findings argue that extensive changes in heterochromatic properties are not enough to alter chromatin conformation at expanded CAG/CTG repeat loci. We conclude that 3D chromatin conformation is unlikely to drive repeat expansions or changes in gene expression in expanded CAG/CTG repeat disorders. This SuperSeries is composed of the SubSeries listed below.
2020-04-07 | GSE148185 | GEO
Project description:Transcription profiles were obtained for 2-month old mice containing an expanded or normal CAG trinucleotide repeat in the coding region for TATA-binding protein (TBP). Three different genotypes were used : TBP-13Q (normal), TBP-71Q (71 repeats), and TBP-105Q (105 repeats). Two lines of TBP-71Q (lines 16 and 27) were used in these experiments. <br><br> The 71Q and 105Q mice express a mutant version of the protein (TBP) and faithfully model the disease SCA17 (spinocerebellar ataxia-17, huntington disease-like 4, HDL4). <br><br> The constructs containing mixed CAG/CAA trinucleotide repeats (and encoding polyglutamine tracts) of variable length were made using a previously described method (Michalik A et al., Biotechniques, 2001). Briefly, synthetic CAG/CAA oligonucleotides were subcloned into a cDNA construct of the normal mouse (13 CAG/CAA) TBP gene. Because of the mixed nature of the repeat, its length is stable in mitotic and meiotic transmission.
2007-11-09 | E-MEXP-1313 | biostudies-arrayexpress
Project description:Whole genome sequence (WGS) data was generated on 3,001 samples previously quantified for the presence of the C9orf72 repeat expansion (212 expanded and 2,789 wild type), These samples were sequenced using a combination of 2x100bp reads on an Illumina HiSeq2000 and 2x150bp reads on an Illumina HiSeqX sequencer. The repeat expansions were called using ExpansionHunter to demonstrate the ability to call large repeats from high throughput, WGS data. Provided here are all read pairs where at least one of the reads aligns within 1kb of the C9orf72 repeat expansion in addition to reads aligned in pre-determined off target locations where the aligners are known to mis-align reads.
| EGAS00001002598 | EGA
Project description:Dentatorubral–pallidoluysian atrophy (DRPLA) is a devastating genetic disease presenting myoclonus, epilepsy, ataxia, and dementia. DRPLA is caused by the expansion of a CAG repeat in the ATN1 gene. The expanded CAG repeats are unstable, and ongoing repeat expansions contribute to disease onset, progression and severity. Previously, we characterized a small molecule, naphthyridine–azaquinolone (NA), which binds to CAG slip-out structures and induces repeat contraction in Huntington’s disease mice. Here, we demonstrate that long-term intracerebroventricular infusion of NA leads to repeat contraction in a murine model of DRPLA. To identify the effects of NA on transcriptional regulation, we conducted comprehensive gene expression analysis using RNA sequencing (RNA-Seq) in striatum from PBS-treated and NA-treated DRPLA mice.
2022-09-08 | GSE183652 | GEO
Project description:Whole genome sequence (WGS) data was generated on 3,001 samples previously quantified for the presence of the C9orf72 repeat expansion (212 expanded and 2,789 wild type), These samples were sequenced using a combination of 2x100bp reads on an Illumina HiSeq2000 and 2x150bp reads on an Illumina HiSeqX sequencer. The repeat expansions were called using ExpansionHunter to demonstrate the ability to call large repeats from high throughput, WGS data. Provided here are all read pairs where at least one of the reads aligns within 1kb of the C9orf72 repeat expansion in addition to reads aligned in pre-determined off target locations where the aligners are known to mis-align reads.
| EGAS00001003383 | EGA