Ontology highlight
ABSTRACT:
PROVIDER: PRJNA532328 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8882810_1.fastq.gz | Fastqsanger.gz | |||
| SRR8882810_2.fastq.gz | Fastqsanger.gz | |||
| SRR8882801.fastq.gz | Fastqsanger.gz | |||
| SRR8882801_1.fastq.gz | Fastqsanger.gz | |||
| SRR8882801_2.fastq.gz | Fastqsanger.gz |
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Project description:Rare monogenic diseases affect millions worldwide; although over 4,500 rare disease genotypes are known, disease-modifying drugs are available for only 5% of them. The sheer number of these conditions combined with their rarity precludes traditional costly drug discovery programs. An economically viable alternative is to repurpose established drugs for rare diseases. Many genetic diseases result from increased or decreased protein activity and identification of clinically approved drugs which moderate this pathogenic dosage holds therapeutic potential. To identify such agents for neurogenetic diseases, we have generated genome-wide transcriptome profiles of mouse primary cerebrocortical cultures grown in the presence of 218 blood brain barrier penetrant clinic-tested drugs. RNAseq and differential expression analyses were used to generate transcriptomic profiles; therapeutically relevant drug-gene interactions related to rare neurogenetic diseases identified in this fashion were further analyzed by qRT-PCR, western blot and immunofluorescence. We have created a transcriptome-wide searchable database for easy access to the gene expression data resulting from the cerebrocortical drug screen (Neuron Screen) and have mined this data to identify a novel link between thyroid hormone and expression of the peripheral neuropathy associated gene Pmp22. Our results demonstrate the utility of cerebrocortical cultures for transcriptomic drug screening, and the database we have created will foster further discovery of novel links between over 200 clinic-tested blood brain barrier penetrant drugs and genes related to diverse neurologic conditions.
2018-09-07 | GSE110256 | GEO
Project description:<p>Garrod’s concept of “chemical individuality” has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant-metabolite associations (P<1.25x10^-11) within 330 genomic regions, with rare variants (MAF≤1%) explaining 9.4% of associations. Jointly modelling metabolites in each region, we identified 423 regional, co-regulated, variant-metabolite clusters called GIMs (Genetically Influenced Metabotypes). We assigned causal genes for 62.4% of GIMs, providing new insights into fundamental metabolite physiology and their clinical relevance, including metabolite guided discovery of potential adverse drug effects (<em>DPYD</em>, <em>SRD5A2</em>). We show strong enrichment of Inborn Errors of Metabolism (IEM)-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of IEMs. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential aetiological relationships.</p><p><br></p><p><strong>EPIC-Norfolk study assays</strong> are reported in the current study <strong>MTBLS833</strong></p><p><strong>INTERVAL study assays</strong> are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS834' rel='noopener noreferrer' target='_blank'><strong>MTBLS834</strong></a></p>
2022-09-09 | MTBLS833 | MetaboLights
Project description:Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding an NF-kB activator within skin epidermis, account for PSORS2. Here we describe fifteen additional rare, missense variants in CARD14, their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls), and their effects on NF-kB activation and the transcriptome of keratinocytes. There was an excess of rare variants within CARD14 in cases versus controls (burden test p-value = 0.0015). Some variants were only seen in a single case and included putative pathogenic mutations (c.424G>A [p.Glu142Lys], c.425A>G [p.Glu142Gly]) and the generalized pustular psoriasis mutation, c.413A>C (p.Glu138Ala), that lie within the coiled-coil domain of CARD14. The c.349G>A (p.Gly117Ser) familial psoriasis mutation was present at a frequency of 0.0005 in cases of European ancestry. CARD14 variants led to a range of NF-kB activities, with putative pathogenic variants leading to levels >2.5-fold higher than wildtype CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with TNF-a to achieve significant increases in NF-kB levels. Transcriptome profiling of wildtype and variant CARD14 transfectants in keratinocytes differentiated likely pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD14 polymorphisms were also genotyped and meta-analysis revealed association of psoriasis with rs11652075 (c.2458C>T/p.Arg820Trp; p-value = 2.1x10-6). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw*0602 (PSORS1). These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease. Keratinocytes were transfected with wildtype Cardsh or one of 16 Card14 mutations (17 total samples). The cells were collected and RNA extracted to determine the effect of these mutations compared to wildtype Card14. No replicates are included.
2012-05-08 | E-GEOD-36381 | biostudies-arrayexpress
Project description:<p>Garrod’s concept of “chemical individuality” has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant-metabolite associations (P<1.25x10^-11) within 330 genomic regions, with rare variants (MAF≤1%) explaining 9.4% of associations. Jointly modelling metabolites in each region, we identified 423 regional, co-regulated, variant-metabolite clusters called GIMs (Genetically Influenced Metabotypes). We assigned causal genes for 62.4% of GIMs, providing new insights into fundamental metabolite physiology and their clinical relevance, including metabolite guided discovery of potential adverse drug effects (<em>DPYD</em>, <em>SRD5A2</em>). We show strong enrichment of Inborn Errors of Metabolism (IEM)-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of IEMs. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential aetiological relationships.</p><p><br></p><p><strong>INTERVAL study assays</strong> are reported in the current study <strong>MTBLS834</strong></p><p><strong>EPIC-Norfolk study assays</strong> are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS833' rel='noopener noreferrer' target='_blank'><strong>MTBLS833</strong></a></p>
2022-09-09 | MTBLS834 | MetaboLights
Project description:Dorrance Rare Childhood Center Transcriptomic and Genomic Studies For Known and Unknown Genetic Etiology
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Project description:Dorrance Rare Childhood Center Transcriptomic and Genomic Studies For Known and Unknown Genetic Etiology
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Project description:Inherited metabolic diseases belong to the group of rare diseases (so called ‘orphan diseases’) whose incidence is less than 1: 5 000 live births. Among these diseases the lysosomal storage diseases (LSD) are also distinguished, which are caused by disorders in the lysosomal system resulting from the mutations in the genes coding for lysosomal hydrolases, cofactors, enzymes involved in the posttranslational processing, and proteins present in the lysosomal membrane. Although about 70 LSD are recognized so far, their pathomechanism is almost unknown. Hitherto existing results of scientific investigations indicate that different cellular pathways and events are involved in the pathogenic processes: autophagy, apoptosis, toxic action of lyso- derivatives of lipid compounds, disordered Ca2+ ions intracellular homeostasis, secondary storage of macromolecular compounds, signal transduction, inflammatory processes, deficient by-products and many more. We are especially interested in the explanation of pathomechanisms of Gaucher disease and Niemann-Pick type C disease (for the latter disease there is no therapy officially accepted). In this project we aim to experimentally explain: - which cellular pathways and mechanisms are activated and inactivated in cells originating from patients with different LSD and healthy individuals - are there differences in genes expression in different diseases - are gene expression changes related to known and observed biochemical and clinical changes.
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Project description:LMNA mutations cause laminopathies, a group of rare genetic diseases with no known cure, only symptomatic treatment and supportive care. In this study, we characterized five LMNA mutations (LMNA(L35P), LMNA(A539V), LMNA(W520G), LMNA(E358K), and LMNA(R453W)) identified from patients diagnosed with muscular laminopathy in the zebrafish model.
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Project description:Defects of the endosomal and lysosomal systems have been increasingly linked to adult neurodegenerative diseases1,2. Deficiencies in the retrograde trafficking pathway between endosomes and the Golgi apparatus lead to forms of Alzheimer’s and Parkinson’s diseases in the case of retromer mutations, or to the rare progressive cerebello-cerebral atrophy type 2 (PCCA2) for mutations of the Golgi-associated retrograde protein (GARP) complex3. Mutations in GARP subunits lead to abnormal cellular lipid metabolism, with accumulation of sterol esters and sphingoid bases, and concomitant lysosomal dysfunction in yeast, murine, or human cells4,5. However, whether these lipid changes cause neurodegeneration and if so, which lipids are toxic, is unknown. Here, we show that GARP defects lead to global changes of cellular protein distribution, including missorting of numerous disease-linked enzymes of sphingolipid metabolism, and to the accumulation of sphingolipid intermediates in wobbler fibroblasts. Inhibiting sphingolipid synthesis in wobbler mice, a murine model of GARP deficiency with features of amyotrophic lateral sclerosis (ALS), improved wellness scores and grip strength, and increased lifespan. Our findings indicate that regulation of sphingolipids by the GARP complex is essential for neuronal health and suggest that inhibition of sphingolipid synthesis might provide a therapeutic strategy for treatment of neurodegenerative diseases due to defects in retrograde endosome-to-Golgi membrane trafficking.
2022-02-15 | PXD007981 | Pride