Down Syndrome

2017 ◽  
Author(s):  
George T Capone
Keyword(s):  
Down Syndrome ◽  
Trisomy 21 ◽  
Developmental Delays ◽  
Gene Dosage ◽  
Adult Life ◽  
Chromosome 21 ◽  
Extra Copy ◽  
Anatomical Features ◽  
Primary Mechanism ◽  
Dosage Imbalance

People with Down syndrome (trisomy 21) are distinguished by having an extra copy of chromosome 21. Chromosome 21 contains an estimated 562 genes, including 161 known to code for functional proteins, and at least 396 considered novel. Gene dosage imbalance is the primary mechanism, which results in the molecular, cellular, histological, and anatomical features characteristic of the condition. Throughout brain development, major neurobiological events go awry, resulting in a differently organized brain and characteristic developmental delays noted during infancy and the preschool years. The consequences of gene dosage imbalance continue to have repercussions on neurobiological function throughout childhood and adult life.

scholarly journals Consequences of aneuploidy in human fibroblasts with trisomy 21

2020 ◽  
Author(s):  
Sunyoung Hwang ◽  
Paola Cavaliere ◽  
Rui Li ◽  
Lihua Julie Zhu ◽  
Noah Dephoure ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Trisomy 21 ◽  
Human Fibroblasts ◽  
Fold Increase ◽  
Trisomy 13 ◽  
Chromosome 21 ◽  
Phenotypic Analysis ◽  
Extra Copy ◽  
Protein Levels ◽  
Post Transcriptional Regulation

AbstractAn extra copy of chromosome 21 causes Down syndrome, the most common genetic disease in humans. The mechanisms by which the aneuploid status of the cell, independent of the identity of the triplicated genes, contributes to the pathologies associated with this syndrome are not well defined. To characterize aneuploidy driven phenotypes in trisomy 21 cells, we performed global transcriptome, proteome, and phenotypic analysis of primary human fibroblasts from individuals with Patau (trisomy 13), Edwards (trisomy 18), or Down syndromes. On average, mRNA and protein levels show a 1.5 fold increase in all trisomies with a subset of proteins enriched for subunits of macromolecular complexes showing signs of post-transcriptional regulation. Furthermore, we show several aneuploidy-associated phenotypes are present in trisomy 21 cells, including lower viability and an increased dependency on the serine-driven lipid biosynthesis pathway to proliferate. Our studies present a novel paradigm to study how aneuploidy contributes to Down syndrome.

scholarly journals Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of down syndrome-related phenotypes

2021 ◽  
Author(s):  
Eva Lana-Elola ◽  
Heather Cater ◽  
Sheona Watson-Scales ◽  
Simon Greenaway ◽  
Jennifer Müller-Winkler ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Cognitive Deficits ◽  
Trisomy 21 ◽  
Heart Defects ◽  
Chromosome 21 ◽  
Phenotypic Analysis ◽  
Extra Copy ◽  
Human Chromosome 21 ◽  
Complex Phenotypes ◽  
Physiological Systems

Down syndrome (DS), trisomy 21, results in many complex phenotypes including cognitive deficits, heart defects and craniofacial alterations. Phenotypes arise from an extra copy of human chromosome 21 (Hsa21) genes. However, these dosage-sensitive causative genes remain unknown. Animal models enable identification of genes and pathological mechanisms. The Dp1Tyb mouse model of DS has an extra copy of 63% of Hsa21-orthologous mouse genes. In order to establish if this model recapitulates DS phenotypes, we comprehensively phenotyped Dp1Tyb mice using 28 tests of different physiological systems and found that 468 out of 1800 parameters were significantly altered. We show that Dp1Tyb mice have wide-ranging DS-like phenotypes including aberrant erythropoiesis and megakaryopoiesis, reduced bone density, craniofacial changes, altered cardiac function, a pre-diabetic state and deficits in memory, locomotion, hearing and sleep. Thus, Dp1Tyb mice are an excellent model for investigating complex DS phenotype-genotype relationships for this common disorder.

scholarly journals Folate pathway metabolites are altered in the plasma of subjects with Down syndrome: relation to chromosomal dosage

2021 ◽  
Author(s):  
Beatrice Vione ◽  
Chiara Locatelli ◽  
Giacomo Zavaroni ◽  
Angela Piano ◽  
Giorgia La Rocca ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Carbon Cycle ◽  
Trisomy 21 ◽  
Metabolic Diseases ◽  
Gene Dosage ◽  
Chromosome 21 ◽  
Congenital Defects ◽  
Control Subjects ◽  
Folate Pathway ◽  
The One

AbstractDown syndrome (DS) is the most common chromosomal disorder, and it is caused by trisomy of chromosome 21 (Hsa21). Subjects with DS can show a large heterogeneity of phenotypes and congenital defects and the most constant clinical features present are typical facies and intellectual disability (ID). Jérôme Lejeune was the first who hypothesized that DS could be a metabolic disease and he noted an alteration of the folate pathway (part of the one-carbon cycle) in trisomic cell lines and subjects with DS. Comparing DS with other metabolic diseases characterized by ID and altered folate pathway he hypothesized a possible correlation among them. Recently, a nuclear magnetic resonance (NMR) analysis of the detectable metabolic part in plasma and urine samples was performed, comparing a group of subjects with DS and a group of control subjects. The data showed a clear difference in the concentration of some metabolites (all involved in central metabolic processes) for the DS group, which was sometimes in agreement with gene dosage expected proportions (3:2). The aim of this work is to underline metabolic differences between subjects with DS and control subjects in order to better understand the dysregulation of the folate pathway in DS. For the first time, we performed enzyme-linked immunosorbent assays (ELISAs) to identify the concentration of 4 different intermediates of the one-carbon cycle, namely tetrahydrofolate (THF), 5-methyl-THF, 5-formyl-THF and S-adenosyl-homocysteine (SAH) in plasma samples obtained from 153 subjects with DS and 54 euploid subjects. Results highlight specific alterations of some folate pathway related metabolites. The relevance of these results for the biology of intelligence and its impairment in trisomy 21 is discussed leading to the proposal of 5-methyl-THF as the best candidate for a clinical trial aimed at restoring the dysregulation of folate pathway in trisomy 21 and improving cognitive skills of subjects with DS.

scholarly journals Congenital Chylothorax in Newborn with Trisomy 21

2021 ◽  
Keyword(s):  
Down Syndrome ◽  
Trisomy 21 ◽  
Rare Complication ◽  
Extra Chromosome ◽  
Chromosome 21 ◽  
Abnormal Development ◽  
Chromosomal Anomalies ◽  
Extra Copy ◽  
Genetic Abnormalities ◽  
Congenital Chylothorax

Dawn syndrome Trisomy 21 means there’s an extra copy of chromosome 21 in every cell. This is the most common form of Down syndrome, there is three types of Down syndrome. Trisomy 21 which there is an extra copy of chromosome 21 in every cell. Mosaicism occurs when a child is born with an extra chromosome in some but not all of their cells. Translocation in this type of Down syndrome, children have only an extra part of chromosome 21. There are 46 total chromosomes. However, one of them has an extra piece of chromosome 21 attached. Down syndrome is associated with a lots of complication like congenital heart disease. Vision. Hearing behavior and mental problem. Our case is Down syndrome with congenital chylothorax which is rare complication. Neonatal chylothorax results from the accumulation of chyle in the pleural space and may be either congenital or an acquired condition. Congenital chylothorax is most likely due to abnormal development or obstruction of the lymphatic system. It is often associated with hydrops fetalis. It can be idiopathic or may be associated with various chromosomal anomalies including Trisomy 21, Turner syndrome, Noonan syndrome, and other genetic abnormalities [1]. Treatment of chylothorax is multidisplenery need insertion of chest tube to decrease respiratory distress, diet management and pediatric surgery.

scholarly journals Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of Down Syndrome-related phenotypes

2021 ◽  
Author(s):  
Eva Lana-Elola ◽  
Heather Cater ◽  
Sheona Watson-Scales ◽  
Simon Greenaway ◽  
Jennifer Müller-Winkler ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Bone Density ◽  
Cognitive Deficits ◽  
Trisomy 21 ◽  
Heart Defects ◽  
Chromosome 21 ◽  
Phenotypic Analysis ◽  
Extra Copy ◽  
Human Chromosome 21 ◽  
Complex Phenotypes

AbstractDown syndrome (DS), trisomy 21, results in many complex phenotypes including cognitive deficits, heart defects and craniofacial alterations. Phenotypes arise from an extra copy of human chromosome 21 (Hsa21) genes. However, causative genes remain mostly unknown. Animal models enable identification of these genes and pathological mechanisms. The Dp1Tyb mouse model of DS has an extra copy of 63% of Hsa21-orthologous mouse genes. Here, we comprehensively phenotype Dp1Tyb mice and find wide-ranging DS-like phenotypes including aberrant megakaryopoiesis, reduced bone density, and deficits in memory, locomotion, hearing and sleep. Thus, Dp1Tyb mice are an excellent model for studies of many complex DS phenotypes.

Trisomy of Erg is required for myeloproliferation in a mouse model of Down syndrome

Blood ◽  
2010 ◽  
Vol 115 (19) ◽  
pp. 3966-3969 ◽  
Author(s):  
Ashley P. Ng ◽  
Craig D. Hyland ◽  
Donald Metcalf ◽  
Catherine L. Carmichael ◽  
Stephen J. Loughran ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Trisomy 21 ◽  
Progenitor Cell ◽  
Gene Dosage ◽  
Myeloproliferative Disorder ◽  
Chromosome 21 ◽  
Loss Of Function ◽  
Hematologic Disorders ◽  
Acute Megakaryocytic Leukemia

Abstract 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(1716)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(1716)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.

scholarly journals What Causes Down Syndrome?

2021 ◽  
Author(s):  
Emine Ikbal Atli
Keyword(s):  
Risk Factors ◽  
Down Syndrome ◽  
Trisomy 21 ◽  
Maternal Age ◽  
Extra Chromosome ◽  
Advanced Maternal Age ◽  
Chromosome 21 ◽  
Human Phenotype ◽  
Meiosis I ◽  
Dosage Imbalance

Trisomy 21 (Down Syndrome) is the model human phenotype for all genome gain-dosage imbalance situations, including microduplications. Years after the sequencing of chromosome 21, the discovery of functional genomics and the creation of multiple cellular and mouse models provided an unprecedented opportunity to demonstrate the molecular consequences of genome dosage imbalance. It was stated years ago that Down syndrome, caused by meiotic separation of chromosome 21 in humans, is associated with advanced maternal age, but defining and understanding other risk factors is insufficient. Commonly referred to as Down syndrome (DS) in humans, trisomy 21 is the most cited genetic cause of mental retardation. In about 95% of cases, the extra chromosome occurs as a result of meiotic non- nondisjunction (NDJ) or abnormal separation of chromosomes. In most of these cases the error occurs during maternal oogenesis, especially in meiosis I.

Chromosome 21 Encoded RUNX1 and ETS-2 Overexpression in Regenerating Hematopoiesis in Children with Down Syndrome - Implications for Leukemiogenesis?.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4373-4373
Author(s):  
Dirk Reinhardt ◽  
Kristin Wortmann ◽  
Miriam Kolar ◽  
Jan H. Klusmann ◽  
Ulrike Puhlmann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Down Syndrome ◽  
Trisomy 21 ◽  
Bone Marrow Cells ◽  
Gene Dosage ◽  
Gene Array ◽  
Chromosome 21 ◽  
Children With Down Syndrome ◽  
Increased Risk ◽  
Hematological Disorder

Abstract Children with Down Syndrome (DS) are at an 150 fold increased risk to develop acute megakaryoblastic leukemia (AMKL) within the first 4 years of life. About 10% of newborns with trisomy 21 showed transient myeloproliferative disorder (TMD). Although mutations of the transcriptional factor GATA1, resulting in the shortened GATA1s have been shown in almost all blasts in DS-AMKL and TMD the predisposition to leukemiogenesis related to trisomy 21 is not clear. TMD occurred during embryonic stress hematopoiesis leading to the hepatic proliferation of the GATA1s positive blasts. Typically blasts disappeared within the first 3 month of live, however after a median time of 1.3years (0.6 to 3.7 years) 20% of the children suffered AMKL and required intensive cytostatic treatment. The expression of chromosome 21 encoded hematological transcription factors (TFs) such RUNX1, ETS-2 and ERG were analysed in leukemic blasts from DS- TMD(n=7), DS-AMKL (n=25), DS without hematological disorder (n=10), AMKL (n=10) and healthy controls (n=7) by qRT-PCR. Results: No increase of RUNX1, ETS-2 and ERG expression could be shown. By contrast, ERG was decrease in all leukemias and in DS without hematological disorder (p Anova.<0.002). GATA1s was significantly overexpressed in TMD and DS-AMKL (pAnova <0.02), whereas GATA1 expression in AMKL and controls was not changed. GATA2 was elevated (pAnova <0.01) in all megakaryoblastic leukemias, with or without DS (pAnova <0.0001). PU.1, typically associated with early lymphatic differentiation and granulopoiesis was down regulated in all megakaryoblastic leukemias and, surprisingly, in DS without hematological disorder. This confirmed previously reported results by gene-array analysis1. To get further insight in the predisposition caused by trisomy 21 we analysed regenerating hematopoiesis in DS (n=14) partly resembling embryonic stress hematopoiesis. Correlated to the amount of bone marrow activation (CD38 positivity) a myeloid cell population (CD13/CD33 positive); with the co-expression of CD56 (NCAM) and CD36 (thrombospondin-receptor) could be detected by immunophenotyping (median percentage all nucleated bone marrow cells: 73±10%). In children without DS but regenerating hematopoiesis (n=41) a similar population of 4.6±1.8% (p<0.00001) could be detected. For further analysis the CD33/CD56 positive cells were sorted (FACSVantage). The cells showed normal myeloid morphology and differentiation, lack of GATA1s mutation, but an aberrant TF expression pattern. RUNX1 was 10-fold and ETS-2 5-fold higher expressed compared to controls (p<0.012). Summarized, (1) DS-AMKL and TMD leukemic blasts showed no general gene-dosage effect. However, (2) in stimulated bone marrow (stress hematopoiesis) trisomy 21 led to an overexpression of chromosome 21 encoded TFs, which might contribute to leukemiogenesis.

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