Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA359353 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The Dp1Tyb mouse model for Down syndrome contains a duplication of 23Mb of mouse chromosome 16 (Mmu16) that is orthologous to human chromosome 21 (Hsa21). This region contains 145 coding genes, and thus these genes are present in 3 copies. Dp1Tyb mice display congenital heart defects, similar to the ones seen in people with Down syndrome. These defects include ventricular and atrio-ventricular septal defects and are seen at embryonic day 14.5 (E14.5) of gestation. One of the 145 genes present in 3 copies in Dp1Tyb mice codes for a kinase called DYRK1A. We found that by crossing Dp1Tyb mice with mice carrying a heterozygous Dyrk1a loss of function allele, thereby reducing the dosage of the Dyrk1a gene from 3 to 2 copies, we rescue the congenital heart defects. Thus 3 copies of Dyrk1a are required to cause heart defects, and, presumably, increased DYRK1A protein is required for the heart defects. We compared the phosphoproteome in Dp1Tyb versus Dp1TybDyrk1a+/+/- embryonic hearts in order to discover alterations in phosphoproteins that could pinpoint molecular mechanisms that give rise to the congenital heart defects. The two strains (Dp1Tyb and Dp1TybDyrk1a+/+/-) differ only in the copy number of Dyrk1a (3 v 2) and thus differences in phosphoproteins would include both direct and indirect targets of DYRK1A activity.
2024-02-01 | PXD013053 | Pride
Project description:Embryos from the Dp1Tyb mouse model for Down syndrome (DS) present with congenital heart defects similar to the heart defects seen in humans with DS. We found that genetically reducing the copy number of the Dyrk1a gene (one of the genes in 3 copies in DS) from 3 to 2, normalised some of the transcriptomic changes in Dp1Tyb embryonic hearts and rescued congenital heart defects. Here we treated pregnant mice carrying Dp1Tyb and wild-type (WT) embryos with a Dyrk1a pharmacological inhibitor (Leucettinib-21 or L21) or an inactive isomer (Iso-L21) to study the effect of L21 on the transcriptome of Dp1Tyb and WT embryonic hearts.
2024-01-25 | GSE239798 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE34457: Molecular Signatures of cardiac defects in Down syndrome lymphoblastoid cell lines (congenital heart disease) GSE34458: Molecular Signatures of cardiac defects in Down syndrome lymphoblastoid cell lines (trisomy 21) Refer to individual Series
2012-08-14 | E-GEOD-34459 | biostudies-arrayexpress
Project description:Identification of Copy Number Variants in Patients with Hypoplastic Left Heart Syndrome and Other Congenital Heart Defects
| PRJNA275738 | ENA
Project description:Molecular Signatures of cardiac defects in Down syndrome lymphoblastoid cell lines. In this study, we want to identify genes and pathways specifically dysregulated in atrioventricular septal defect and /or atrial septal defect + ventricular septal defect in case of trisomy 21. Total RNA obtained from DS lymphoblastoid cell lines without congenital heart disease compared to cell lines from DS with congenital heart disease.
2012-08-14 | E-GEOD-34457 | biostudies-arrayexpress
Project description:Congenital development disorders with variable severity occur in trisomy 21. However, how these phenotypic abnormalities develop with variations remains elusive. We hypothesize that the difference in euploidy gene expression variation among trisomy 21 tissues are perturbed by the presence of an extra copy of chromosome 21 and this may contribute to the phenotypic variations in Down syndrome. Keywords: Disease state analysis
2008-03-18 | GSE10758 | GEO
Project description:Individuals with Down syndrome (DS) are at an increased risk for developing congenital heart defects especially atrioventricular septal defects (AVSD). Our goal was to identify the contribution of copy number variants (CNV) to DS-associated AVSD. We used the Affymetrix SNP 6.0 genotyping platform to comprehensively characterize CNVs in 452 ethnically matched individuals with DS, comprising of 210 cases (DS + complete AVSD) and 242 controls with a structurally normal heart (DS + NH). Results from burden and region-wise analyses using PLINK revealed that despite the 2000 fold elevated risk, common CNVs of large effect (OR > 2.0) do not account for the increased risk observed in DS-associated AVSD. In contrast, cases do harbor a significantly elevated burden of large rare variants (> 100kb, < 1% frequency) (p < 0.01) and case deletions intersect genes more often than those observed in controls (p < 0.007). Gene enrichment analysis showed a trend for enrichment among deletions impacting the ciliome pathway in cases compared to controls. Our findings suggest that the etiology of AVSD is highly complex and does not arise from the action of a few common variants of large effect. Instead, our data support a multifactorial model, wherein large rare deletions play a significant role in elevating the risk of AVSD in a trisomic background. Copy Number Variation Analysis of individuals with DS using Affymetrix SNP 6.0 genotyping platform. A composite reference was generated using the same dataset to derive the log2 ratios using Affymetrix Power Tols (APT). Submitting here the preliminary data from 437 subjects, 15 were excluded due to privacy concerns.
2014-10-24 | E-GEOD-60607 | biostudies-arrayexpress
Project description:Dysregulation of Sonic hedgehog (SHH) signaling may contribute to multiple Down syndrome-associated phenotypes, including cerebellar hypoplasia, congenital heart defects, craniofacial and skeletal dysmorphologies, and Hirschsprung disease. Granule cell precursors isolated from the developing cerebellum of Ts65Dn mice are less responsive to the mitogenic effects of SHH than euploid cells, and a single postnatal dose of the SHH pathway agonist SAG rescues cerebellar morphology and performance on learning and memory tasks in Ts65Dn mice. SAG treatment also normalizes expression levels of OLIG2 in neural progenitor cells derived from human trisomy 21 iPSCs. However, despite evidence that activating SHH signaling rescues Down syndrome-associated phenotypes, chromosome 21 does not encode any canonical components of the SHH pathway. Here, we screened 163 chromosome 21 cDNAs in a series of SHH-responsive cell lines to identify chromosome 21 genes that modulate SHH signaling and confirmed overexpression of trisomic candidate genes using RNA-seq in Ts65Dn and TcMAC21 cerebellum. Our study indicates that some chromosome 21 genes, including DYRK1A, activate SHH signaling while others, such as HMGN1 and MIS18A, inhibit SHH signaling. Moreover, overexpression of genes involved in chromatin structure and mitosis, but not genes previously implicated in ciliogenesis, regulate the SHH pathway. Our data suggest that cerebellar hypoplasia and other phenotypes related to aberrant SHH signaling arise from the net effect of trisomy for multiple chromosome 21 genes rather than the overexpression of a single trisomic gene. Identifying which chromosome 21 genes modulate SHH signaling may also suggest new therapeutic avenues for ameliorating Down syndrome phenotypes.
2022-05-16 | GSE202938 | GEO
Project description:Congenital development disorders with variable severity occur in trisomy 21. However, how these phenotypic abnormalities develop with variations remains elusive. We hypothesize that the difference in euploidy gene expression variation among trisomy 21 tissues are perturbed by the presence of an extra copy of chromosome 21 and this may contribute to the phenotypic variations in Down syndrome. Experiment Overall Design: We used DNA microarray to measure the differences in gene expression variance (representing variation) between four human trisomy 21 amniocytes and six human euploid amniocytes.
2008-04-03 | E-GEOD-10758 | biostudies-arrayexpress
Project description:One in five people with Down syndrome (DS) are born with an atrioventricular septal defect (AVSD), an incidence 2,000 times higher than in the euploid population. The genetic loci that contribute to this risk are poorly understood. In this study, we tested two hypotheses: 1) individuals with DS carrying chromosome 21 copy number variants (CNVs) that interrupt exons may be protected from AVSD, because these CNVs return AVSD susceptibility loci back to disomy, and 2) individuals with DS carrying chromosome 21 genes spanned by microduplications are at greater risk for AVSD because these microduplications boost the dosage of AVSD susceptibility loci beyond a tolerable threshold. We tested 236 case individuals with DS+AVSD and 290 control individuals with DS and a normal heart using a custom microarray with dense probes tiled on chromosome 21 for array CGH. We found that neither an individual chromosome 21 CNV nor any individual gene intersected by a CNV was associated with AVSD in DS. Burden analyses revealed that African American controls had more bases covered by rare deletions than did African American cases. Inversely, we found that Caucasian cases had more genes intersected by rare duplications than did Caucasian controls. Pathway analyses indicated copy number perturbtations of genes involved in protein heterotrimerization and histone methylating proteins. Finally, we showed that previously DS+AVSD-associated common CNVs on chromosome 21 are likely false positives. This research adds to the swell of evidence indicating that DS-associated AVSD is similarly heterogeneous, as is AVSD in the euploid population.
2017-01-30 | GSE93004 | GEO