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Human chromosome 21 is the smallest human autosome and many important genetic/familial disorders map to this chromosome, e.g., familial amyotrophic lateral sclerosis (FALS), Down syndrome, Alzheimer's disease and some cases of Ewings sarcoma. Hence, the identification of genes localised to this chromosome and studies on their normal biological func...
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... syndrome (Fig. 6) or trisomy 21 is the most common chromosomal abnormality that comes to term in humans (33). It occurs at a rate of 1 in 700 live births. It is also the most common cause of mental retardation amongst humans. Further, individuals with Down syndrome develop abnormalities of every major organ system, including the deposition of brain ...
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Segmentation is a standard method of data analysis to identify change-points dividing a nonstationary time series into homogeneous segments. However, for long-range fractal correlated series, most of the segmentation techniques detect spurious change-points which are simply due to the heterogeneities induced by the correlations and not to real nons...
Thesis (Ph. D.)--University of Wisconsin--Madison, 2001. Includes bibliographical references. Photocopy.
It is well established that changes in the phenotype depend much more on changes in gene expression than on changes in protein-coding genes, and that cis-regulatory sequences and chromatin structure are two major factors influencing gene expression. Here, we investigated these factors at the genome-wide level by focusing on the trinucleotide patter...
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... However, despite the whole chromosome sequencing, no highly critical genes have been identified in this region to account for all the various phenotypes associated with DS (Delabar et al. 1993). Models for understanding the DS critical regions, mouse genome has been analysed (Kola et al. 1997) Reymond et al. 2002). The trisomy of chromosome 21 category. ...
Background: Down syndrome, caused due to trisomy of chromosome 21. Methods: 131 suspected cases of DS from university hospital after obtaining written informed consent clinical history and photographs were also recorded. Diagnosis carried out by tacking peripheral blood from the children, setting up whole blood culture as well as DNA extraction from leukocytes for molecular analysis. G-banding by Saline-Trypsin-Giemsa (STG) method and Karyotyping. Results: They were into four categories using automated Karyotyper. Category 1, out of 131 96(73.28%) cases of these had trisomy 21 while Category 2, showed 3(2.29%) cases with translocation or isochromosome involving chromosome 21. Category 3, was 0 mosaics cases. Category 4, was 0, will be karyotypically 46,/XY but show partial duplications case. An unusual Down syndrome is Category 5, had remaining 32(24.42%) cases, though referred for DS were karyotypically 46,XX or 46,XY. Of these only one cases were judiciously selected and tested for partial duplication of Down syndrome critical region (DSCR) with the help of FISH by using LSI 21 chromosome 21 specific probe but as such no duplication was observed. One of the above two case was further investigated through oligo-based cytogenetic array for micro-duplication or deletion of region on chromosome 21 other than the DSCR and it revealed no duplication or deletion of any part of chromosome 21 or whole genome. Conclusion: This study suggested besides trisomy 21 and chromosomal rearrangements there might be genetic imbalances leading to perturbations of pathway/s could result unusual Down syndrome.
... Adult Down syndrome (DS) patients, who mostly carry trisomy 21 in their genome, unanimously develop the neuropathological changes of AD (Lott and Head, 2019). Besides amyloid precursor protein gene, four of the six IFN receptors, IFNAR1, IFNAR2, IFNGR2, and IL10RB, are encoded in the extra chromosome 21, which results in profound peripheral IFN response and autoinflammation in DS patients (Kola and Hertzog, 1997;Sullivan et al., 2016Sullivan et al., , 2017. Interestingly, mice bearing trisomy 16, which contains many orthologs from human trisomy 21, benefited from receiving antibodies blocking type I IFN (IFNα/β) and type II IFN (IFNγ) at development stage in vivo, whereas blocking IFNγ signaling rescued the premature death of trisomy 16 cortical neurons in vitro (Maroun, 1995;Hallam and Maroun, 1998;Hallam et al., 2000). ...
Alzheimer’s disease (AD) represents an enormous public health challenge currently and with increasing urgency in the coming decades. Our understanding of the etiology and pathogenesis of AD is rather incomplete, which is manifested in stagnated therapeutic developments. Apart from the well-established Amyloid Hypothesis of AD, gaining traction in recent years is the Pathogen Hypothesis, which postulates a causal role of infectious agents in the development of AD. Particularly, infection by viruses, among a diverse range of microorganisms, has been implicated. Recently, we described a prominent antiviral immune response in human AD brains as well as murine amyloid beta models, which has consequential effects on neuropathology. Such findings expectedly allude to the question about viral infections and AD. In this Perspective, we would like to discuss the molecular mechanism underlying the antiviral immune response, highlight how such pathway directly promotes AD pathogenesis, and depict a multilayered connection between antiviral immune response and other agents and factors relevant to AD. By tying together these threads of evidence, we provide a cohesive perspective on the uprising of antiviral immune response in AD.
... It should be noted that the specific genetic implications of DS, such as altered collagen formations, may result in impaired bone development that may or may not be observed in individuals with ID from other causes (Hattori et al., 2000;Kola & Hertzog, 1997;Parsons, Ryan, Reeves, & Richtsmeier, 2007;Pozsonyi, Gibson, & Zarfas, 1964). Therefore, it is important to examine individuals with DS as a distinct group when conducting studies of bone health in people with ID. ...
... The DS participants and ID participants of this study portrayed similar levels of physical activity, yet the DS participants had significantly lower BMD than the ID participants. There were no significant correlations between physical activity and BMD as seen previously (Aspray et al., 1998); however, the findings of this study may give credence to the theory that gene driven developmental issues in the cartilage of participants with DS exist (Hattori et al., 2000;Kola & Hertzog, 1997;Parsons et al., 2007;Pozsonyi et al., 1964). Abnormal cartilage maturation patterns may be responsible for decreased BMD as well as Figure 1. ...
... Differing letters above bars signify significant differences between groups at p , 0.001. diminished growth rates of individuals with DS (Garcia-Ramirez et al., 1998;Hattori et al., 2000;Kola & Hertzog, 1997;Parsons et al., 2007;Pozsonyi et al., 1964). ...
Abstract Individuals with intellectual disability (ID) or Down syndrome (DS) may be at greater risk of osteoporosis. The purpose of this study was to compare bone mineral density (BMD) of DS, ID, and non-intellectually disabled (NID) populations. In each group, 33 participants between the ages of 28 and 60 years were compared. BMD was measured with dual-energy x-ray absorptiometry (DXA) scans. BMD (p < .0001) between all groups was significantly different. Participants with DS had significantly lower BMD compared to NID participants. Individuals with ID had significantly lower BMD compared to NID subjects. Participants with DS had the lowest BMD of all groups. DS subjects display a greater risk for osteoporosis than ID subjects or control populations.
... Along with intellectual disability compromised immunity, hormonal alteration, predisposition to malignancy etc. are of frequent occurrence in individuals with DS. Although trisomy of the 21st chromosome (HSA21) as a whole or triplication of genes in the Down syndrome critical region, leading to an over expression of these genes, may be one of the key factor for DS [2], it is still uncertain whether DS and its associated physiological abnormalities could be caused by particular gene loci in HSA21 [3]. Single minded 2 (SIM2) and V-ets erythroblastosis virus E26 oncogene homolog 2 (ETS2) are two transcription factors located in HSA21 and are over expressed in individuals with DS [1]. ...
Trisomy of the 21{st} chromosome leads to an over dosage of several regulatory genes in Down syndrome (DS). Though allelic and genotypic combinations formed between genes are interesting, till date, this particular area has never been explored in DS. In the present investigation four SNPs in two transcription factors, Single minded 2 (SIM2) and V-ets erythroblastosis virus E26 oncogene homolog2 (ETS 2 ), located in the 21{st} chromosome were genotyped to understand their role in DS. Genomic DNA of eastern Indian probands with DS (N=132), their parents (N=209) and ethnically matched controls (N=149) was subjected to PCR-based analyses of functionally important SNPs followed by statistical analyses. ETS2 rs461155 showed high heterozygosity in DS. Significantly lower frequency of SIM2 C-G haplotype (rs2073601-rs2073416) was noticed in individuals with DS (P value =0.01669) and their fathers (P value=0.01185). Significantly lower frequency of the A-C-C-G with higher frequency of A-C-A-G haplotypes was also noticed in subjects with DS (P value =0.02089 and 0.00588 respectively). Data obtained indicate that the rs2073601 'A' allele, responsible for nonsynonymous substitution of leucine to methionine, may have some role in DS in this population.
... Morphological abnormalities of the dendritic spines have been demonstrated in the brains of Ts65Dn mice , the most used model of DS (Kola and Hertzog, 1997), in which hippocampal neurons exhibit major abnormal induction of both LTP and LTD due to enhanced recruitment of synaptic interneuronal inhibition (Fernandez et al., 2007;Kleschevnikov et al., 2004;Siarey et al., 1999). However, two recent studies conducted a more in-depth analysis of hippocampal plasticity changes in DS concluding that alterations of functional connectivity in the hippocampal network rather than LTP machinery impairment or molecular changes in synaptic constitution might . ...
... Morphological abnormalities of the dendritic spines have been demonstrated in the brains of Ts65Dn mice , the most used model of DS (Kola and Hertzog, 1997), in which hippocampal neurons exhibit major abnormal induction of both LTP and LTD due to enhanced recruitment of synaptic interneuronal inhibition (Fernandez et al., 2007;Kleschevnikov et al., 2004;Siarey et al., 1999). However, two recent studies conducted a more in-depth analysis of hippocampal plasticity changes in DS concluding that alterations of functional connectivity in the hippocampal network rather than LTP machinery impairment or molecular changes in synaptic constitution might . ...
Memory impairment is commonly associated with epilepsy, and the use of antiepileptic drugs (AEDs) causes additional neuropsychologic deficits that are of particular concern in learning-age children and elderly patients. The aim of this study was to investigate hippocampal synaptic plasticity and morphology as well as hippocampal-dependent memory in physiologic conditions and in a genetic model of epilepsy following chronic treatment with the widely used AED valproic acid (VPA).
Mice lacking the presynaptic scaffolding protein Bassoon were used as a model of epilepsy. Electrophysiologic recordings were used to analyze basal glutamatergic synaptic transmission, paired-pulse facilitation, and activity-dependent long-term potentiation (LTP) in the CA1 area. Dendritic morphology and spine density were analyzed, and glutamate-related signaling was investigated by Western blot analysis. Social transmission of food preference test was used to investigate nonspatial hippocampal memory.
VPA treatment significantly reduced seizures frequency and mortality in epileptic mice. Long-term potentiation was absent at CA1 synapses of untreated epileptic mutant mice that also showed significant dendritic abnormalities. Treatment with VPA rescued physiologic LTP but did not reverse morphological abnormalities and deficits in nonspatial hippocampal memory observed in mutant epileptic mice. Moreover, VPA was found to induce per se dendritic abnormalities and memory dysfunction in normal animals.
The impairment of hippocampal synaptic plasticity in epileptic mice, rescued by VPA treatment, might represent the mechanism underlying epilepsy-induced memory deficits. Moreover, the demonstration that VPA induces morphologic alterations and impairment in specific hippocampal-dependent memory task might explain the detrimental effects of antiepileptic treatment on cognition in human subjects.
... Therefore, mice trisomic for chromosome 16 have been generated and investigated as a mouse model for Down syndrome. However, mice with additional entire chromosome 16 (Ts16) never survive the first day of birth and most frequently die during late gestation (Kola and Hertzog 1997;Hattori, Fujiyama et al. 2000;Guigo, Dermitzakis et al. 2003). However, during embryonic development these mice show anatomic features that are reminiscent of Down syndrome (Lacey-Casem and Oster-Granite 1994), and newborn animals have significant morphological, biochemical and immunological similarities to DS individuals (Kola and Hertzog 1997;Hattori, Fujiyama et al. 2000;Guigo, Dermitzakis et al. 2003). ...
... However, mice with additional entire chromosome 16 (Ts16) never survive the first day of birth and most frequently die during late gestation (Kola and Hertzog 1997;Hattori, Fujiyama et al. 2000;Guigo, Dermitzakis et al. 2003). However, during embryonic development these mice show anatomic features that are reminiscent of Down syndrome (Lacey-Casem and Oster-Granite 1994), and newborn animals have significant morphological, biochemical and immunological similarities to DS individuals (Kola and Hertzog 1997;Hattori, Fujiyama et al. 2000;Guigo, Dermitzakis et al. 2003). Therefore, the use of mouse model is still one of the most promising approaches to understand DS pathology. ...
GIRK2 is located on chromosome 21, which trisomy is the cause of Down syndrome (DS). In DS, among other features, proportions of T lymphocytes subpopulations are altered and number of circulating B cells are decreased. We hypothesized that it is due to the disturbed control of homing/recirculation of lymphocytes by endothelial cells (ECs). ECs constitute the vessel wall, achieve the neovascularisation, interact with circulating cells, initiate the adhesion process thus, immunological response. To assess the GIRK2 gene influence on the function of ECs, an in vitro cellular model was established. ECs lines were established from bone marrow, thymus, peripheral lymph nodes, Peyer's patches and brain from transgenic mice with additional copies of the gene and from normal control mice. Endothelium biology was investigated in the aspect of adhesion molecules as well as processes of adhesion and angiogenesis. ECs from transgenic mice have altered levels of CD29, CD34, their adhesive properties towards lymphoid cells are affected and their angiogenic properties are drastically different. cDNA microarray display for the gene expression pattern of ECs from transgenic mice showed that among adhesion molecules, chemokines, chemokine receptors, VEGFs and VEGFs receptors, more than one fourth of the mRNA was significantly modified compared to controls. Presented results give clear evidence that GIRK2 gene can influence the function of endothelial cells in DS patients.
... This anomaly likely underlies the reduction in hippocampal LTP noted in an earlier study (Siarey et al., 1997). However, not every gene found on chromosome 21 in humans is triplicated in these mice (Kola and Hertzog, 1997;Gardiner et al., 2003), and the animal models are far from perfect. Nonetheless, the Ts65Dn model will be useful in assessing the effects of very specific changes in the Sim2 and drebrin on dendritic spines. ...
... However, the deficits are not in complete agreement with data reported from human Down's syndrome individuals. The Ts65Dn mouse model contains triplication of only 108 of the genes located on human chromosome 21, which has an estimated 250 -1000 genes (Kola and Hertzog, 1997;Galdzicki and Siarey, 2003). For some aspects of Down's syndrome, the mouse model is ideal. ...
The work presented in this dissertation represents investigations into the mechanism of two neurological disorders. The first set of experiments was aimed at examining the morphology of post-synaptic structures called dendritic spines in a mouse model of Down’s syndrome. The second set of experiments was aimed at examining the regional pattern and cellular distribution of possible therapeutic targets, histone deacetylases, in treating the symptoms of Huntington’s disease.
In the first set of experiments, we examined a mouse model of Down’s syndrome, the Ts65Dn mouse, to determine if it mimics the dendritic spine abnormalities in area CA1 of hippocampus that have been documented in human individuals with the disorder. The Ts65Dn mouse represents a partial trisomy of the murine chromosome homologous to a large portion of human chromosome 21, which is present in 3 copies rather than 2 in Down’s syndrome. These mice show behavioral abnormalities and learning deficits that are thought to replicate the mental retardation that is a prominent characteristic of Down’s syndrome. As many of the behavioral and learning paradigms used to test these mice require hippocampal function, and neurons from hippocampal tissue taken from Down’s syndrome individuals show a reduction in the density of dendritic spines, we sought to determine if Ts65Dn mice exhibit the same morphological abnormality.
Dendritic spine densities on the apical branches of CA1 hippocampal neurons in Ts65Dn animals were not significantly different when compared to those from euploid (normal chromosome number) littermates. In addition, morphological analysis of dendritic spine shape demonstrated that the proportion of dendritic spines in each of the four major spine shape categories (stubby, thin, filopodia and mushroom) was not different between the two conditions. As the environment for cells in a cultured slice are most likely very different from those experienced in the intact animal, we examined if neurons in the intact brain exhibited signs of abnormal dendritic spine density in the Ts65Dn mouse. Analysis of dendritic spine densities on apical branches of CA1 hippocampal neurons from mice sacrificed at 2 weeks, 3 months or 6 months of age showed no significant differences between the euploid and trisomic conditions. Furthermore, Western blot analysis showed that Ts65Dn do not have reduced expression of a dendritic spine protein, drebrin, as has been reported in Down’s syndrome.
The second set of experiments that are described concern the immunohistochemical localization of two enzymes involved in the transcriptional regulation of genes. These enzymes, called histone deacetylases, or HDACs, aid in the regulation of histone acetylation levels as a mechanism to control access of transcription factors to gene sequences. Recently, it was found that compounds that inhibit enzymes that remove acetyl groups demonstrate therapeutic effects in animal models of Huntington’s disease, a neurodegenerative disorder that targets brain regions important for movement control. The work presented here describes the immunohistochemical localization of a HDAC2 and HDAC7.
HDAC7 immunohistochemistry was consistent with biochemical studies demonstrating that HDAC7 can be present in both the cytoplasm and the nucleus. A finding of interest is that not all neurons of the murine brain express HDAC7, nor is it localized to the same subcellular compartment in all cell types. Granule cells of the hippocampal dentate gyrus and of the cerebellum showed very little immunoreactivity for HDAC7. Apical dendrites of the CA1 and CA3 regions of hippocampus showed very heavy cytoplasmic staining. Deeper cortical layers showed pyramidal neurons with heavier staining than superficial pyramidal layers in almost all cortical regions, except for the orbital, insular and piriform cortices which showed heavy staining in superficial layers as well. In general, staining of the olfactory system appeared more intense than other sensory system regions. Fibers along the striatonigral bundle, from the caudate to the substantia nigra reticulata showed heavy immunoreactivity. These data suggest that targeting therapeutics to HDAC7 activity may indeed be useful, as the striatonigral pathway is a key component of movement control.
HDAC2 immunoreactivity confirmed that HDAC2 is strictly a nuclear localized protein. In addition, it appeared that HDAC2 is ubiquitously expressed throughout the murine brain in all brain regions. Interestingly, HDAC2 staining occurred only in neurons that showed NeuN staining, demonstrating that it is a neuron-specific protein. Therefore, therapeutic inhibition of HDACs that include inhibition of HDAC2 may affect many aspects of neurologic functioning in multiple brain regions.
It is our hope that this work will provide some added detail and knowledge to the greater neuroscience community, and will aid in the greater understanding of the organization and function of the brain and ultimately aid in development of treatments for and ultimately the cure of neurological diseases and disorders.
... DS-like phenotypes identified in the Ts43H and Ts16 models could be due to three copies of Hsa21 orthologs, trisomy of large genomic regions, or trisomic heterogeneity that disturbs distinct pathways but leads to similar phenotypes. Transgenic mouse models with single Hsa21 orthologous genes or regions at dosage imbalance have also been created (Altafaj et al. 2001;Ema et al. 1999;Kola and Hertzog 1997;Roubertoux et al. 2006;Smith et al. 1997). These models, along with mice that have a specific gene or region knocked out or deleted, provide valuable data for understanding gene function, especially when analyzed in parallel with segmental trisomy models. ...
Since the genetic basis for Down syndrome (DS) was described, understanding the causative relationship between genes at dosage imbalance and phenotypes associated with DS has been a principal goal of researchers studying trisomy 21 (Ts21). Though inferences to the gene-phenotype relationship in humans have been made, evidence linking a specific gene or region to a particular congenital phenotype has been limited. To further understand the genetic basis for DS phenotypes, mouse models with three copies of human chromosome 21 (Hsa21) orthologs have been developed. Mouse models offer access to every tissue at each stage of development, opportunity to manipulate genetic content, and ability to precisely quantify phenotypes. Numerous approaches to recreate trisomic composition and analyze phenotypes similar to DS have resulted in diverse trisomic mouse models. A murine intraspecies comparative analysis of different genetic models of Ts21 and specific DS phenotypes reveals the complexity of trisomy and important considerations to understand the etiology of and strategies for amelioration or prevention of trisomic phenotypes. By analyzing individual phenotypes in different mouse models throughout development, such as neurologic, craniofacial, and cardiovascular abnormalities, greater insight into the gene-phenotype relationship has been demonstrated. In this review we discuss how phenotype-based comparisons between DS mouse models have been useful in analyzing the relationship of trisomy and DS phenotypes.
... We determined the normal values of lymphocyte subpopulations of physiologic fetuses during the course of pregnancy. The clinical signifi cance lies in the fi nding of basic differences in the fetal immune system in comparison to adults and in the possibility of prenatal diagnosis of congenital defects of immunity [11] including the study of the reaction of the fetal immune system to various stress stimuli. On a representative population of fetuses with DS, using comparison with physiologic fetuses of same gestational age, we demonstrated that the immunologic defect of these affected fetuses is already present antenatally and can be reliably diagnosed in the second trimester of pregnancy. ...
Lymphocyte subpopulations are identified by the uniform CD classification (Cluster of Differentiation) and can be accurately differentiated with monoclonal antibodies using the method of flow cytometry. With the aid of cordocentesis it is possible to perform studies on the status and development of cellular immunity as early as in the second trimester of pregnancy.
To compare lymphocyte subpopulations present in fetuses with chromosomal abnormalities (Down's syndrome (DS), Edwards' syndrome (ES)) and fetuses with normal karyotype.
Prospective observational study.
We examined a total of 61 pregnant women with an average age of 31.5 years (20- 46 years).
In fetuses with DS we found a significant decrease in B lymphocytes (CD19),a decrease in the subpopulations of multi-reactive B-cells (CD5(+)CD19(+), B-CLL),and a decrease in the index of CD4/CD8 and class II HLA-DR. In contrast, the representation of NK cells expressing /CD3-CD (16 + 56)+/ was greatly increased. In ES we found a decrease in T lymphocytes (CD3), a decrease in T-helper lymphocytes (monocytes CD4), a decreased index of CD4/CD8 and a greater representation of NK cells /CD3-CD (16 + 56)+/.
We determined the normal values of lymphocyte subpopulations in physiological fetuses. We demonstrated that the immunological defect of the affected fetuses is already present antenatally, and can be reliably diagnosed in the second trimester of pregnancy.
