Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013080 (Down syndrome)
14,180 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To contribute to the development of the transcription map of human chromosome 21 (HC21), we have used exon trapping from pools of HC21-specific cosmids. Using selected trapped exons, we have identified a novel gene (named TMPRSS2) that encodes a multimeric protein with a serine protease domain. The TMPRSS2 3.8-kb mRNA is expressed strongly in small intestine and weakly in several other tissues. The full-length cDNA encodes a predicted protein of 492 amino acids that contains the following domains: (i) A serine protease domain (aa 255-492) of the S1 family that probably cleaves at Arg or Lys residues. (ii) An SRCR (scavenger receptor cysteine-rich) domain (aa 149-242) of group A (6 conserved Cys). This type of domain is involved in the binding to other cell surface or extracellular molecules. (iii) An LDLRA (LDL receptor class A) domain (aa 113-148). This type of domain forms a binding site for calcium. (iv) A predicted transmembrane domain (aa 84-106). No typical signal peptide was recognized. The gene was mapped to 21q22.3 between markers ERG and D21S56 in the same P1 as MX1. The physiological role of TMPRSS2 and its involvement in trisomy 21 phenotypes or monogenic disorders that map to HC21 are unknown.
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PMID:Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22.3. 932 52

The region of chromosome 21 between genes CBR and ERG (CBR-ERG region), which spans 2.5 Mb on 21q22.2, has been defined by analysis of patients with partial trisomy 21. It contributes significantly to the pathogenesis of many characteristics of Down syndrome, including morphological features, hypotonia, and mental retardation. Cosmid contigs covering 80% of the region were constructed and EcoRI maps produced. These cosmids were used for exon trapping and cDNA selection from three cDNA libraries (fetal brain, fetal liver, and adult skeletal muscle). Isolated exons and cDNAs were mapped on the EcoRI map, organized into contigs, sequenced, and used as probes for Northern blot analysis of RNA from fetal and adult tissues. We identified 27 genuine or highly probable transcriptional units evenly distributed along the CBR-ERG region. Eight of the transcriptional units are known genes.
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PMID:Transcriptional map of the 2.5-Mb CBR-ERG region of chromosome 21 involved in Down syndrome. 950 11

We have isolated two novel genes, designated DSCR5 and DSCR6, from the Down syndrome critical region (DSCR) on chromosome 21q22.2 which has been defined as minimal overlapping region of partial trisomy 21 patients and located between t(4;21) break point and ERG (approximately 1.6 Mb). DSCR5 and DSCR6 genes consist of 6 and 5 exons, respectively. Alternative use of transcription start sites and alternative splicing events produce different RNA species and proteins from both genes. Three different transcripts of DSCR5 gene encode three putative transmembrane proteins of 158, 134, and 108 amino acids, while 4 different transcripts of DSCR6 gene encode two forms of proteins with 190 and 106 amino acids. The DSCR5 gene is expressed in various human tissues examined, whereas the DSCR6 gene is expressed only in limited tissues at low level. Both DSCR5 and DSCR6 genes are candidates for the pathogenesis of Down syndrome, although the function of these genes remains to be elucidated.
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PMID:Isolation of two novel genes, DSCR5 and DSCR6, from Down syndrome critical region on human chromosome 21q22.2. 1081 24

We have carried out a detailed annotation of 550 kb of genomic DNA on human chromosome 21 containing the ERG and ETS2 genes. Comparative genomic analysis between this region and the interval of conserved synteny on mouse chromosome 16 indicated that the order and orientation of the ERG and ETS2 genes were conserved and revealed several regions containing potential conserved noncoding sequences. Four pseudogenes including those for small protein G, laminin receptor, human transposase protein and meningioma-expressed antigen were identified. A potentially novel gene (C21orf24) with alternative mRNA transcripts, consensus splice donor and acceptor sites, but no coding potential nor murine orthologue, was identified and found to be expressed in a range of human cell lines. We have identified four novel splice variants that arise from a previously undescribed 5' exon of the human ERG gene. Comparison of the cDNA sequences enabled us to determine the complete exon-intron structure of the ERG gene. We have also identified the presence of noncoding RNAs in the first and second introns of the ETS2 gene. Our studies have important implications for Down syndrome as this region contains multiple mRNA transcripts, both coding and potentially noncoding, that may play as yet undescribed roles in the pathogenesis of this disorder.
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PMID:Detailed mapping of the ERG-ETS2 interval of human chromosome 21 and comparison with the region of conserved synteny on mouse chromosome 16. 1469 72

Down syndrome (DS; trisomy 21) is a genetic disorder associated with early mental retardation and patients inevitably develop Alzheimer's disease (AD)-like neuropathological changes. The molecular defects underlying the DS-phenotype may be due to overexpression of genes encoded on chromosome 21. This so-called gene dosage hypothesis is still controversial and demands systematic work on protein expression. A series of transcription factors (TF) are encoded on chromosome 21 and are considered to play a pathogenetic role in DS. We therefore decided to study brain expression of TF encoded on chromosome 21 in patients with DS and AD compared to controls: Frontal cortex of 6 male DS patients, 6 male patients with AD and 6 male controls were used for the experiments. Immunoblotting was used to determine protein levels of TF BACH1, ERG, SIM2 and RUNX1. SIM2 and RUNX1 were comparable between groups, while BACH1 was significantly reduced in DS, and ERG was increased in DS and AD as compared to controls. These findings may indicate that DS pathogenesis cannot be simply explained by the gene dosage effect hypothesis and that results of ERG expression in DS were paralleling those in AD probably reflecting a common pathogenetic mechanism possibly explaining why all DS patients develop AD like neuropathology from the fourth decade. We conclude that TF derangement is not only due to the process of neurodegeneration and propose that TFs BACH1 and ERG play a role for the development of AD-like neuropathology in DS and pathogenesis of AD per se and the manifold increase of ERG in both disorders may form a pivotal pathogenetic link.
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PMID:Aberrant protein expression of transcription factors BACH1 and ERG, both encoded on chromosome 21, in brains of patients with Down syndrome and Alzheimer's disease. 1506 37

There is a series of about 12 transcription factors expressed on chromosome 21. These transcription factors (TFs) are major candidates for playing a pathogenetic role for the abnormal wiring of the brain in fetal Down Syndrome (DS) as approximately 5,000 TFs are developmentally involved in the complex architecture of the human brain. TF derangement in DS has been already reported and we decided to contribute to the problem by studying four TFs encoded on chromosome 21 in fetal DS brain. We used fetal cortex of 8 DS fetuses and 6 controls (females) from the 18-19th week of gestation. Brain homogenates were subject to immunoblotting using goat-anti-BACH1, rabbit anti-heme oxygenase 1 (HO1), rabbit anti-ERG, rabbit anti-RUNX1 and goat anti-SIM2 l. Antibodies against beta-actin were used to normalise cell loss and antibodies against neuron-specific enolase were used to compensate neuronal loss. BACH1 was significantly overexpressed in fetal DS (p < 0.008) as compared to controls whereas RUNX1 and ERG proteins were comparable between groups, and SIM2 l was not detectable in any specimen. BACH1 was even significantly increased in the DS panel when normalised versus the housekeeping protein beta-actin (p < 0.01) or the neuron specific enolase (p < 0.01). HO-1 was found comparable between groups. BACH1, a member of the family of BTB-basic leucine zipper transcription factors, regulates gene expression through the NF-E2 site. More specifically, BACH1 suppresses expression of HO1. Increased BACH1, however, did not lead to decreased HO1, which would have explained oxidative stress observed in fetal DS.
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PMID:Overexpression of transcription factor BACH1 in fetal Down syndrome brain. 1506 51

Aneuploidy is one of the hallmarks of cancer. Acquired additions of chromosome 21 are a common finding in leukemias, suggesting a contributory role to leukemogenesis. About 10% of patients with a germ line trisomy 21 (Down syndrome) are born with transient megakaryoblastic leukemia. We and others have shown acquired mutations in the X chromosome gene GATA1 in all these cases. The gene or genes on chromosome 21 whose overexpression promote the megakaryoblastic phenotype are presently unknown. We propose that ERG, an Ets transcription factor situated on chromosome 21, is one such candidate. We show that ERG is expressed in hematopoietic stem cells, megakaryoblastic cell lines, and in primary leukemic cells from Down syndrome patients. ERG expression is induced upon megakaryocytic differentiation of the erythroleukemia cell lines K562 and UT-7, and forced expression of ERG in K562 cells induces erythroid to megakaryoblastic phenotypic switch. We also show that ERG activates the gpIb megakaryocytic promoter and binds the gpIIb promoter in vivo. Furthermore, both ERG and ETS2 bind in vivo the hematopoietic enhancer of SCL/TAL1, a key regulator of hematopoietic stem cell and megakaryocytic development. We propose that trisomy 21 facilitates the occurrence of megakaryoblastic leukemias through a shift toward the megakaryoblastic lineage caused by the excess expression of ERG, and possibly by other chromosome 21 genes, such as RUNX1 and ETS2, in hematopoietic progenitor cells, coupled with a differentiation arrest caused by the acquisition of mutations in GATA1.
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PMID:The proto-oncogene ERG in megakaryoblastic leukemias. 1614 Sep 24

This report describes the first identification and characterization of three chromosome-21-specific DNA sequences (and reference sequences from other chromosomes) that are differentially methylated between peripheral blood and placental tissue, with the aim of providing epigenetic biomarkers for quantifying cell-free fetal DNA in maternal plasma. To select sequences to be screened for differential methylation, three strategies were adopted: (i) investigating promoters of highly differentially expressed genes; (ii) choosing 'random' promoter regions; and (iii) choosing 'random' non-promoter regions. Over 200 pre-selected DNA sequences were screened using a methylation-specific restriction enzyme assay. Differentially methylated sequences located at 21q22.3 (AIRE, SIM2 and ERG genes), 1q32.1 (CD48 gene and FAIM3 gene), 2p14 (ARHGAP25 gene) and 12q24 (SELPLG gene) were identified. Bisulphite conversion confirmed that CpG sites within the AIRE promoter region are highly differentially methylated, and optimized methylation-specific primers for this region that are highly specific for placental DNA were devised. Next, it was shown that the methylation status of chorionic villus sample DNA from first trimester pregnancies matched the hypermethylated state of term placenta. Thus there is no indication of a difference in methylation status between early and term pregnancy for the sequences tested. The identified sequences constitute candidate biomarkers for non-invasive prenatal diagnosis of Down syndrome.
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PMID:Candidate epigenetic biomarkers for non-invasive prenatal diagnosis of Down syndrome. 1769 2

ETS2 and ERG are transcription factors, encoded on human chromosome 21 (Hsa21), that have been implicated in human cancer. People with Down syndrome (DS), who are trisomic for Hsa21, are predisposed to acute megakaryoblastic leukemia (AMKL). DS-AMKL blasts harbor a mutation in GATA1, which leads to loss of full-length protein but expression of the GATA-1s isoform. To assess the consequences of ETS protein misexpression on megakaryopoiesis, we expressed ETS2, ERG, and the related protein FLI-1 in wild-type and Gata1 mutant murine fetal liver progenitors. These studies revealed that ETS2, ERG, and FLI-1 facilitated the expansion of megakaryocytes from wild-type, Gata1-knockdown, and Gata1s knockin progenitors, but none of the genes could overcome the differentiation block characteristic of the Gata1-knockdown megakaryocytes. Although overexpression of ETS proteins increased the proportion of CD41(+) cells generated from Gata1s-knockin progenitors, their expression led to a significant reduction in the more mature CD42 fraction. Serial replating assays revealed that overexpression of ERG or FLI-1 immortalized Gata1-knockdown and Gata1s knockin, but not wild-type, fetal liver progenitors. Immortalization was accompanied by activation of the JAK/STAT pathway, commonly seen in megakaryocytic malignancies. These findings provide evidence for synergy between alterations in GATA-1 and overexpression of ETS proteins in aberrant megakaryopoiesis.
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PMID:ETS2 and ERG promote megakaryopoiesis and synergize with alterations in GATA-1 to immortalize hematopoietic progenitor cells. 1985 Jul 50

Down syndrome is characterized by multiple phenotypic manifestations associated with trisomy of chromosome 21. The transient myeloproliferative disorder and acute megakaryocytic leukemia associated with Down syndrome are uniquely associated with mutations in the transcription factor GATA1; however, the identity of trisomic genes on chromosome 21 that predispose to these hematologic disorders remains unknown. Using a loss-of-function allele, we show that specific reduction to functional disomy of the Erg gene corrects the pathologic and hematologic features of myeloproliferation in the Ts(17(16))65Dn mouse model of Down syndrome, including megakaryocytosis and progenitor cell expansion. Our data provide genetic evidence establishing the need for Erg trisomy for myeloproliferation in Ts(17(16))65Dn mice and imply that increased ERG gene dosage may be a key consequence of trisomy 21 that can predispose to malignant hematologic disorders in Down syndrome.
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PMID:Trisomy of Erg is required for myeloproliferation in a mouse model of Down syndrome. 2046 69


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