Exome & MiSeq sequencing of individuals with Huntington's disease
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001006383 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Recent data strongly suggest HTT CAG repeat expansion drives Huntington’s disease (HD) pathogenesis and that disease development is modulated by components of the DNA damage response (DDR) pathway. FAN1 has been identified as a major HD modifier which slows expansion of the HTT CAG repeat in several cell and animal HD models. Here we show dual FAN1 activities act to inhibit repeat expansion. A highly conserved SPYF motif in the FAN1 N-terminus is required for an MLH1 interaction, which slows expansion, with FAN1 nuclease activity also contributing towards repeat stabilisation. Our data supports a model where FAN1 binds MLH1, restricting its recruitment by MSH3 and the formation of the functional DNA mismatch repair (MMR) complex believed to promote CAG repeat expansion. FAN1 nuclease activity functions either concurrently or following MMR activity to maintain repeat stability. These data highlight a potential avenue for HD therapeutics in attenuating somatic expansion.
2022-02-16 | PXD023221 | Pride
Project description:In Huntington’s disease (HD), expanded HTT CAG repeat length correlates strongly with age at motor onset, indicating that it determines the rate of the disease process leading to diagnostic clinical manifestations. Similarly, in normal individuals, HTT CAG repeat length is correlated with biochemical differences that reveal it as a functional polymorphism. Here, we tested the hypothesis that gene expression signatures can capture continuous, length-dependent effects of the HTT CAG repeat. Using gene expression datasets for 107 HD and control lymphoblastoid cell lines, we constructed mathematical models in an iterative manner, based upon CAG correlated gene expression patterns in randomly chosen training samples, and tested their predictive power in test samples. Predicted CAG repeat lengths were significantly correlated with experimentally determined CAG repeat lengths, whereas models based upon randomly permuted CAGs were not at all predictive. Predictions from different batches of mRNA for the same cell lines were significantly correlated, implying that CAG length-correlated gene expression is reproducible. Notably, HTT expression was not itself correlated with HTT CAG repeat length. Taken together, these findings confirm the concept of a gene expression signature representing the continuous effect of HTT CAG length and not primarily dependent on the level of huntingtin expression. Such global and unbiased approaches, applied to additional cell types and tissues, may facilitate the discovery of therapies for HD by providing a comprehensive view of molecular changes triggered by HTT CAG repeat length for use in screening for and testing compounds that reverse effects of the HTT CAG expansion. To evaluate the continuous analytical approach as a strategy to discover the molecular consequences of the HTT CAG repeat, genome-wide gene expression datasets were generated from a panel of 107 human lymphoblastoid cell lines with HTT CAGs spanning the entire spectrum of allele sizes.
2013-05-03 | E-GEOD-34721 | biostudies-arrayexpress
Project description:In Huntington’s disease (HD), expanded HTT CAG repeat length correlates strongly with age at motor onset, indicating that it determines the rate of the disease process leading to diagnostic clinical manifestations. Similarly, in normal individuals, HTT CAG repeat length is correlated with biochemical differences that reveal it as a functional polymorphism. Here, we tested the hypothesis that gene expression signatures can capture continuous, length-dependent effects of the HTT CAG repeat. Using gene expression datasets for 107 HD and control lymphoblastoid cell lines, we constructed mathematical models in an iterative manner, based upon CAG correlated gene expression patterns in randomly chosen training samples, and tested their predictive power in test samples. Predicted CAG repeat lengths were significantly correlated with experimentally determined CAG repeat lengths, whereas models based upon randomly permuted CAGs were not at all predictive. Predictions from different batches of mRNA for the same cell lines were significantly correlated, implying that CAG length-correlated gene expression is reproducible. Notably, HTT expression was not itself correlated with HTT CAG repeat length. Taken together, these findings confirm the concept of a gene expression signature representing the continuous effect of HTT CAG length and not primarily dependent on the level of huntingtin expression. Such global and unbiased approaches, applied to additional cell types and tissues, may facilitate the discovery of therapies for HD by providing a comprehensive view of molecular changes triggered by HTT CAG repeat length for use in screening for and testing compounds that reverse effects of the HTT CAG expansion.
2013-05-03 | GSE34721 | GEO
Project description:<p>Huntington's disease (HD) is a neurodegenerative disorder typically diagnosed in mid-life that is caused by expansion of an otherwise polymorphic CAG trinucleotide repeat. The mutation causes a gain-of-function of the huntingtin protein to trigger a pathogenic process that produces detectable phenotypic differences many years before the traditional diagnosis, which is based upon characteristic motor symptoms. The prediagnosis phase of pathogenesis is now the subject of intense scrutiny by an NINDS-funded longitudinal study, PREDICT-HD, in which undiagnosed gene carriers are followed longitudinally and subjected to detailed phenotyping (PREDICT-HD Huntington Disease Study -- dbGaP Study Accession: <a href="./study.cgi?study_id=phs000222">phs000222</a>). This powerful approach, which offers the potential for moving the focus of therapeutic development to the decades prior to neurological disease diagnosis, is enabled by the fact that all individuals with HD have the same type of mutation, which can be determined at any time in life by a single HD CAG repeat PCR amplification assay. The precise length of the HD CAG repeat differs between individuals. There is a strong negative correlation between the number of CAG repeats and the age at onset of diagnostic neurological abnormalities in HD, such that the CAG repeat accounts for ~50% of the variation in age at diagnosis. Analysis of the remaining variance not explained by the length of the CAG repeat has shown that it is highly heritable, being due to genetic variation, elsewhere in the genome.</p> <p>The intent of the Genetic Modifiers of Huntington's Disease study is to identify genetic modifiers of HD pathogenesis by using genomewide association techniques in diagnosed HD individuals to identify genetic factors associated with the residual variance in age at onset not explained by the CAG repeat, and to extend these analyses to pre-diagnosis phenotypes, for example, those defined in the PREDICT-HD study. Identification of modifier genes is a top priority for HD research (and an example of an approach that can be applied in other late-onset genetic disorders), as it could provide clues to developing rational treatments that delay or prevent the pathogenic process from causing the ravages of the disease that ensue in the ~15 years of inexorable decline to ultimate death that now follows clinical diagnosis.</p> <p>To further that goal, the release of <b>study version 2</b> makes available whole exome sequencing data of n=221 study participants.</p>
| phs000371 | dbGaP
Project description:To study cell type- and HTT CAG length-dependent transcriptional and alternative splicing changes associated with HD, we conducted deep RNA-sequencing analysis on human embryonic stem cells (hESC), NPC and neuron cell lines (ESC and NPC, NEU) expressing wild-type (27/ and 30 CAG repeats), 45 CAG (45Q; representing 45 polyQ mutant HTT protein) and 81 CAG (81Q) repeat expansion HTT gene (n=3). The cell lines were derived from an isogenic HTT CAG repeat expansion allelic cell line panel (IsoHD) where hESC H9 cells were genetically modified with monoallelic knockin of expanded CAG tract in exon 1 of HTT representing early onset (45Q) and late onset (81Q) HD, with the 27Q/30Q genotype as healthy control phenotype (Ooi et al., 2019). The sequencing experiment generated 2.9 billion pairs of 150 bp paired-end reads from 27 samples (3 clones, 3 genotypes, 3 cell lines), with 80 to 110 million read pairs per sample. Transcriptome alignment yielded 75 to 100 million uniquely mapped read pairs across all samples.
2024-09-17 | GSE217469 | GEO
Project description:Huntington's disease (HD) is a severe neurological disease leading to psychiatric symptoms, motor impairment and cognitive decline. The disease is caused by a CAG expansion in the huntingtin (HTT) gene, but how this translates into the clinical phenotype of HD remains elusive. Using liquid chromatography mass spectrometry, we analyzed the metabolome of cerebrospinal fluid (CSF) from premanifest and manifest HD subjects as well as control subjects. Inter-group differences revealed that the tyrosine metabolism, including tyrosine, thyroxine, L-DOPA and dopamine, was significantly altered in manifest compared with premanifest HD. These metabolites demonstrated moderate to strong associations to measures of disease severity and symptoms. Thyroxine and dopamine also correlated with the five year risk of onset in premanifest HD subjects. The phenylalanine and the purine metabolisms were also significantly altered, but associated less to disease severity. Decreased levels of lumichrome were commonly found in mutated HTT carriers and the levels correlated with the five year risk of disease onset in premanifest carriers. These biochemical findings demonstrates that the CSF metabolome can be used to characterize molecular pathogenesis occurring in HD, which may be essential for future development of novel HD therapies.
2019-06-21 | MTBLS749 | MetaboLights
Project description:Huntington’s disease is a dominantly inherited neurodegenerative disease caused by the expansion of a CAG repeat in the HTT gene. In addition to the length of the CAG expansion, factors such as genetic background have been shown to contribute to the age at onset of neurological symptoms. A central challenge in understanding the disease progression that leads from the HD mutation to massive cell death in the striatum is the ability to characterize the subtle and early functional consequences of the CAG expansion longitudinally. We used dense time course sampling between 4 and 20 postnatal weeks to characterize early transcriptomic, molecular and cellular phenotypes in the striatum of six distinct knock-in mouse models of the HD mutation. We studied the effects of the HttQ111 allele on the C57BL/6J, CD-1, FVB/NCr1, and 129S2/SvPasCrl genetic backgrounds, and of two additional alleles, HttQ92 and HttQ50, on the C57BL/6J background. We describe the emergence of a transcriptomic signature in HttQ111/+ mice involving hundreds of differentially expressed genes and changes in diverse molecular pathways. We also show that this time course spanned the onset of mutant huntingtin nuclear localization phenotypes and somatic CAG-length instability in the striatum. Genetic background strongly influenced the magnitude and age at onset of these effects. This work provides a foundation for understanding the earliest transcriptional and molecular changes contributing to HD pathogenesis.
2017-03-01 | GSE88920 | GEO
Project description:<p>The goal of our studies is to identify genetic modifiers of neurodegeneration in Huntington's disease (HD). HD is caused by expansion of CAG repeats in the huntingtin (Htt) gene, with longer stretches often leading to more rapid disease onset and progression. Yet, for a given number of repeats, the age of symptom onset can be variable, differing by up to decades. Thus, the age of onset of motor symptoms in HD is only partly explained by the length of the CAG expansion. Available evidence suggests that genetic modifiers contribute to the variation in HD onset. Identifying genetic modifiers is important because they may provide critical insights into HD pathogenesis and reveal key pathways that could be targeted by novel HD therapeutics. This is important since there are no disease-modifying therapies for HD, and mHtt is an unattractive small-molecule drug target. We recruited 21 HD families with varying characteristics of disease progression and age of onset and obtained medical histories, clinical records and DNA samples that were subjected to whole-genome sequencing (WGS). These WGS data describe families of 104 subjects, including HD patients and their unaffected family members. These individuals were selected based on individual clinical histories and family structures that best fit our criteria for expressing potential genetic modifiers. We are testing the hypothesis that novel, rare genetic variants contribute to HD and those genetic modifiers can be identified by WGS.</p>
| phs001071 | dbGaP
Project description:HD and control patient-derived induced pluripotent stem cells were used to generate medium spiny neuron (MSN)-like cells. Three control in triplicate, one control in duplicate, one HD samples with CAG repeat length in typical adult onset range in triplicate and one in duplicate, and five HD samples with CAG repeat length in typical juvenile onset range in triplicate were differentiated as biological growth replicate (separate differentiations) into medium spiny neuron-like cells. Total RNA was isolated using the Qiagen RNeasy Kit and QIAshredders for cell lysis. 1 µg of RNA with RIN values >9 were used for library preparation using the strand specific Illumina TruSeq Total RNA protocol. Libraries were sequenced on the HiSeq 2500 using 100 cycles to obtain paired-end 100 reads at >50M reads per sample.
2020-03-01 | GSE144559 | GEO
Project description:HD and control patient-derived induced pluripotent stem cells were used to generate medium spiny neuron-like cells. Three control in triplicate, one control in duplicate, one HD samples with CAG repeat length in typical adult onset range in triplicate and one in duplicate, and five HD samples with CAG repeat length in typical juvenile onset range in triplicate were differentiated as biological growth replicate (separate differentiations) into medium spiny neuron-like cells. Total RNA was isolated using the Qiagen RNeasy Kit and QIAshredders for cell lysis. 1 µg of RNA with RIN values >9 were used for library preparation using the strand specific Illumina TruSeq Total RNA protocol. Libraries were sequenced on the HiSeq 2500 using 100 cycles to obtain paired-end 100 reads at >50M reads per sample.
2020-03-01 | GSE144518 | GEO