PCR-free HiSeqX whole genome sequence data on 120 samples with triplet repeat expansions (premutation and full expansions)
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001002462 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Ongoing CAG expansions in Spinocerebellar ataxia type 1 (SCA1) and Huntington disease (HD) brains exacerbate disease. Expansions involve aberrant repair of mutagenic slipped-DNAs, formed from single-stranded DNAs. Whether singlestranded DNA-binding proteins prevent or facilitate expansions is unknown. We assessed canonical RPA (RPA1-RPA2-RPA3) and Alternative-RPA (RPA1-RPA4- RPA3), containing primate-specific RPA4. RPA is essential for all DNA metabolism. Alt-RPA has undefined functions. Alt-RPA is upregulated 10-fold in HD and SCA1 patient brains. RPA enhances, while Alt-RPA blocks, correct repair of slipped-CAGs. RPA, but not Alt-RPA, efficiently binds and melts slipped-DNAs. RPA enhances, while Alt-RPA blocks, removal of excess slipped-DNAs by FAN1 nuclease. Protein-protein interactomes reveal unique and shared partners of RPA and Alt-RPA, including expansion-driving proteins. RPA-overexpression in SCA1 mice inhibits CAG expansions in brains, rescuing neuron morphology and motor phenotypes. Modulating repeat mutations is one example involving antagonistic Alt-RPA↔RPA interactions, illuminating questions as to which RPA-mediated processes are also modulated by AltRPA.
2023-10-13 | PXD044158 | Pride
Project description:CGG repeat expansions in the Fragile X mental retardation 1 (FMR1) gene are responsible for a family of associated disorders characterized by either intellectual disability and autism (Fragile X Syndrome, FXS), or adult-onset neurodegeneration (Fragile X-associated Tremor/Ataxia Syndrome, FXTAS). However, the FMR1 locus is complex and encodes several long noncoding RNAs (lncRNAs), whose expression is altered by repeat expansion mutations. The role of these lncRNAs is thus far unknown; therefore we investigated the functionality of FMR4, which we previously identified. “Full”-length expansions of the FMR1 triplet repeat cause silencing of both FMR1 and FMR4, thus we are interested in potential loss-of-function that may add to phenotypic manifestation of FXS. Since the two transcripts do not exhibit cis-regulation of one another, we examined the potential for FMR4 to regulate target genes at distal genomic loci using gene expression microarrays. We identified FMR4-responsive genes, and further investigated their function related to human neural precursor cells. We therefore propose that FMR4’s function is as a gene-regulatory lncRNA and that this transcript may function in normal development. Closer examination of FMR4 increases our understanding of the role of regulatory lncRNA and the consequences of FMR1 repeat expansions. Study design includes 2 timepoints (6 and 24 hrs post-transfection) x 4 conditions (knockdown & control, overexpression & control) x 3 biological replicates. 3 technical replicates were pooled to creat each biological replicate.
2015-09-01 | E-GEOD-70817 | biostudies-arrayexpress
Project description:CGG repeat expansions in the Fragile X mental retardation 1 (FMR1) gene are responsible for a family of associated disorders characterized by either intellectual disability and autism (Fragile X Syndrome, FXS), or adult-onset neurodegeneration (Fragile X-associated Tremor/Ataxia Syndrome, FXTAS). However, the FMR1 locus is complex and encodes several long noncoding RNAs (lncRNAs), whose expression is altered by repeat expansion mutations. The role of these lncRNAs is thus far unknown; therefore we investigated the functionality of FMR4, which we previously identified. “Full”-length expansions of the FMR1 triplet repeat cause silencing of both FMR1 and FMR4, thus we are interested in potential loss-of-function that may add to phenotypic manifestation of FXS. Since the two transcripts do not exhibit cis-regulation of one another, we examined the potential for FMR4 to regulate target genes at distal genomic loci using gene expression microarrays. We identified FMR4-responsive genes, and further investigated their function related to human neural precursor cells. We therefore propose that FMR4’s function is as a gene-regulatory lncRNA and that this transcript may function in normal development. Closer examination of FMR4 increases our understanding of the role of regulatory lncRNA and the consequences of FMR1 repeat expansions.
2015-09-01 | GSE70817 | GEO
Project description:Transcriptional down regulation caused by intronic triplet repeat expansions underlies diseases such as Friedreich?s ataxia. This down regulation of gene expression is coupled with epigenetic changes but the underlying mechanisms are unknown. Here, we show that an intronic TTC/GAA triplet expansion within the IIL1 gene of Arabidopsis thaliana results in accumulation of 24-nt siRNAs and repressive histone marks at the IIL1 locus, which in turn causes its transcriptional down regulation and an associated phenotype. Knocking down DICER LIKE-3 (DCL3), which produces 24-nt siRNAs, suppressed transcriptional down regulation of IIL1 and the expansion-associated phenotype. Furthermore, knocking down additional components of the RNA-dependent DNA Methylation (RdDM) pathway, also suppressed both transcriptional down regulation of IIL1 and the repeat expansion associated phenotype. Thus our results show that triplet repeat expansions can lead to local siRNA biogenesis, which in turn down regulates transcription through an RdDM-dependent epigenetic modification.
2018-07-25 | GSE113923 | 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: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: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:Whole genome sequence (WGS) data was generated on 58 samples with validated repeat lengths for the CAG repeat associated with Huntington disease, 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, WGS data.
| EGAS00001002593 | EGA
Project description:Transcription profiles were obtained for 2-month old mice. Three lines (WT, TBP-13Q12, and TBP105Q) were used in these experiments. <br><br> Wild-type and 13Q mice are normal. The 13Q mice overexpress the normal protein on the RNA but not protein level and do not show a phenotype. The 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-1314 | biostudies-arrayexpress