890ebf59-9f5b-4bf7-9c1d-435ebdb9de06 - samples
Ontology highlight
ABSTRACT:
PROVIDER: EGAD00001008420 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:TRIP4 is one of the subunits of the transcriptional coregulator ASC-1, a ribonucleoprotein complex that participates in transcriptional coactivation and RNA processing events. Recessive variants in the TRIP4 gene have been associated with spinal muscular atrophy with bone fractures as well as a severe form of congenital muscular dystrophy. Here we present the diagnostic journey of a patient with cerebellar hypoplasia and spinal muscular atrophy (PCH1) and congenital bone fractures. Initial exome sequencing analysis revealed no candidate variants. Reanalysis of the exome data by inclusion in the Solve-RD project resulted in the identification of a homozygous stop-gain variant in the TRIP4 gene, previously reported as disease-causing. This highlights the importance of analysis reiteration and improved and updated bioinformatic pipelines. Proteomic profile of the patient’s fibroblasts showed altered RNA-processing and impaired exosome activity supporting the pathogenicity of the detected variant. In addition, we identified a novel genetic form of PCH1, further strengthening the link of this characteristic phenotype with altered RNA metabolism.
2022-02-16 | PXD023584 | Pride
Project description:Mutation of the gene encoding the ATP-dependent chromatin remodeler CHD7 causes CHARGE syndrome. The mechanisms underlying the neurodevelopmental deficits associated with the syndrome, which include cerebellar hypoplasia, developmental delay, coordination problems and autistic features, are not known. CHD7 is expressed in neural stem and progenitor cells, but its role in neurogenesis during brain development remains unknown. Here we show that deletion of Chd7 from cerebellar granule cell precursors (GCps) in the mouse results in reduced GCp proliferation, cerebellar hypoplasia, developmental delay and motor deficits. Genome-wide expression profiling revealed downregulated Reln gene expression in Chd7-deficient GCps. Recessive RELN mutations is associated with severe cerebellar hypoplasia in humans. We provide molecular and genetic evidence that reduced Reln expression contributes substantially to the GCp proliferative defect and cerebellar hypoplasia in GCp-specific Chd7 mouse mutants. Finally, we show that CHD7 is necessary for the maintenance of an open, accessible chromatin state at the Reln locus. Taken together, this study shows that Reln gene expression is regulated by chromatin remodeling, identifies CHD7 as a previously unrecognized upstream regulator of Reln and provides the first evidence that a mammalian CHD protein controls brain development by modulating chromatin accessibility in neuronal progenitors in vivo.
2017-01-01 | GSE90466 | GEO
Project description:Purine biosynthesis and metabolism, conserved in all living organisms, is essential for cellular energy homeostasis and nucleic acids synthesis. The de novo synthesis of purine precursors is under tight negative feedback regulation mediated by adenine and guanine nucleotides. We describe a new early-onset distinct neurodegenerative condition resulting from mutations in the adenosine monophosphate deaminase 2 gene (AMPD2). Patients have characteristic brain imaging features of pontocerebellar hypoplasia (PCH), due to loss of brainstem and cerebellar parenchyma. We found that AMPD2 plays an evolutionary conserved role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis. AMPD2 deficiency results in defective GTP-dependent initiation of protein translation, which can be rescued by administration of purine precursors. These data suggest AMPD2-related PCH as a new potentially treatable early-onset neurodegenerative disease. An 18 chip study, that compares iPSC derived neural progenitor cells from two individuals: a patient with pontocerebellar hypoplasia and an unaffected parent. Samples are run as either non-treated, treated with Adenosine, or treated with Adenosine and AICAr. Three replicates are included for every individuals in every treatment condition.
2013-12-01 | E-GEOD-46615 | biostudies-arrayexpress
Project description:Cancer cell lines can provide robust and facile biological models for the generation and testing of hypothesis in the early stages of drug development and caner biology. Although clinical trials remain the ultimate scientific testing ground for anticancer therapies, the use of appropriate model systems to explore the molecular basis of drug activity and to identify predictive biomarkers during their development can have a profound effect on the design, cost and ultimate success of new cancer drug development. In order to capture the high degree of genomic diversity in cancer and to identify rare molecular subtypes, we have assembled a collection of >1000 cancer cell lines. These lines have been characterised using whole exome sequencing, genome wide analysis of copy number, mRNA gene expression profiling and DNA methylation analysis (http://cancer.sanger.ac.uk/cell_lines). To further characterise this panel of cell lines we have now compiled data for RNA sequencing. The current study represent data for ~450 of the cell lines in the panel, data for the remaining lines can be accessed via the CGHUB data browser hosted at UCSC. <br>This ArrayExpress record contains only meta-data. Raw data files have been archived at the European Genome-Phenome Archive (EGA, www.ebi.ac.uk/ega) by the consortium, with restricted access to protect sample donors' identity. The relevant accessions of the EGA data set is EGAD00001001357 under EGA study accession EGAS00001000828.
2017-09-25 | E-MTAB-3983 | biostudies-arrayexpress
Project description:The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins, and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Utilizing exome sequencing and extensive international data sharing efforts, we describe 43 affected individuals from 27 unrelated families with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with YnMyr chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (21 males and 22 females), with ages ranging from 1 to 50 years old, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (97%), facial dysmorphism (94%), movement disorders (94%), and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (74%), oculomotor (68%) and behavioural abnormalities (63%), weight gain (59%), microcephaly (38%) and epilepsy (37%). The most conspicuous and common movement disorder was dystonia (90%), frequently leading to early-onset progressive postural deformities (93%), limb dystonia (40%), and cervical dystonia (25%). A jerky tremor in the upper limbs (61%), a mild head tremor (56%), parkinsonism/hypokinesia developing with advancing age (31%), and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (66.6%), hypoplasia/agenesis of the anterior commissure (62.9%), short midbrain and small inferior cerebellar vermis (40.7% each), hypertrophy of the clava (18.5%) were common neuroimaging findings. Acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism, and midbrain defects accompanied with developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localisation and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-Myristoylation was similarly affected in acbd6-deficient zebrafish and Xenopus models, including of FUS, MARCKS and CHCHD-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders.
2024-05-22 | PXD024957 | Pride
Project description:Complex molecular programs in specific cell lineages govern human heart development. Hypoplastic left heart syndrome (HLHS) is the most severe congenital heart defect encompassing a spectrum of left-ventricular hypoplasia occurring in association with outflow-tract obstruction. The current clinical paradigm assumes HLHS is largely of hemodynamic origin. Here, by combining whole-exome sequencing of 87 HLHS parent-offspring trios and transcriptome of cardiomycytes (CMs) from healthy and patient native ventricles at different stages of development we identified perturbations in coherent gene programs controlling ventricular muscle lineage development. Single-cell and 3D molecular/functional modeling with iPSCs demonstrated intrinsic defects in the cell-cycle/ciliogenesis/autophagy hub resulting in disrupted differentiation of early cardiac progenitor (CP) lineages and ultimate defective CM-subtype differentiation/maturation in HLHS. Moreover, premature cellcycle exit of ventricular CM prevents tissue response to cues of developmental growth leading to multinucleation/polyploidy, accumulation of DNA damage, exacerbated apoptosis, and eventually ventricle hypoplasia. Our results highlight how genetic heterogeneity in HLHS converges in perturbations of sequential cellular processes driving cardiogenesis and facilitate potential novel nodes for therapy beside surgical intervention.
2022-02-15 | PXD014812 | Pride
Project description:To evaluate the impact of blood collection tubes on extracellular RNA (exRNA) sequencing, 10 different blood collection tubes were compared by applying RNA Exome sequencing (Illumina) to exRNA from human healthy donor plasma or serum. Three time spans between blood draw and downstream processing were evaluated for each of the tubes. Preservation tubes were processed immediately upon blood collection (T0), after 24 hours (T24), or after 72 hours (T72). Non-preservation plasma and serum tubes were processed immediately upon blood collection (T0), after 4 hours (T4), or after 16 hours (T16). Due to donor privacy concerns the raw data for this study have been submitted to the controlled-access archive EGA under the accession EGAS00001005263.
2021-06-10 | E-MTAB-10507 | biostudies-arrayexpress
Project description:<p>The purpose of this study is to identify new genetic causes of neurodevelopmental diseases (NDDs) in the Joubert syndrome (JS) spectrum. Joubert syndrome is a recessive disease characterized by cerebellar vermis hypoplasia. Our currently funded NINDS award entitled "Molecular characterization of Joubert syndrome" seeks to identify new genetic causes through a variety of molecular strategies. Although our previous strategies involved whole genome SNP-scans, followed by candidate gene sequencing to arrive at identification of new JS causes, we have recently moved to Whole Exome Sequencing (WES) as a highly efficient methodology that is optimized for recessive disease. In this pilot project, CIDR has sequenced DNA on probands from 20 inbred families with JS spectrum disorders in which known causes have been excluded, that have not previously undergone genome-wide SNP scans. These paired end reads will be subject to our established bioinformatics pipeline including HOMOZGYOSITY, SNP and INDEL callers in our lab to identify potentially deleterious sequence changes (PDSC). This is followed by analysis to include testing each PDSC for segregation in the whole pedigree, for occurrence in a ethnically-matched cohort, as well as a defined patient cohort patients, in order to validate new NDD genes.</p>
| phs000382 | dbGaP
Project description:We designed a large scale gene expression study in cerebellar external granular layer in Ts1Cje mice at P0 in order to measure the effects of trisomy 21 on in a enriched cell population (dissected layer) that is affected in Down syndrome in order to correlate gene expression changes to the phenotype observed. Keywords: Down syndrome, Ts1Cje, EGL, hypoplasia We analyzed gene expression in the EGL of Ts1Cje and euploid mice at P0 using pangenomic Illumina mouse-6 v1.1 expression beadchips containing 46 632 probes representing approximately 19 000 mouse genes. 18 samples from individual cerebellar EGL were hybridized on 18 microarrays (6 by slide). On each slide, we hybridized 6 samples frome the same litter.
2008-03-31 | E-GEOD-11472 | biostudies-arrayexpress
Project description:We designed a large scale gene expression study in cerebellar external granular layer in Ts1Cje mice at P0 in order to measure the effects of trisomy 21 on in a enriched cell population (dissected layer) that is affected in Down syndrome in order to correlate gene expression changes to the phenotype observed. Keywords: Down syndrome, Ts1Cje, EGL, hypoplasia
2008-03-31 | GSE11472 | GEO