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Stylianos E Antonarakis - One of the best experts on this subject based on the ideXlab platform.

  • A mouse embryonic stem cell bank for inducible overexpression of human Chromosome 21 genes
    Genome Biology, 2010
    Co-Authors: Rossella De Cegli, Stylianos E Antonarakis, Antonio Romito, Simona Iacobacci, Mario Lauria, Anthony O Fedele, Joachim Klose, Christelle Borel, Patrick Descombes, Diego Di Bernardo
    Abstract:

    Background Dosage imbalance is responsible for several genetic diseases, among which Down syndrome is caused by the trisomy of human Chromosome 21. Results To elucidate the extent to which the dosage imbalance of specific human Chromosome 21 genes perturb distinct molecular pathways, we developed the first mouse embryonic stem (ES) cell bank of human Chromosome 21 genes. The human Chromosome 21-mouse ES cell bank includes, in triplicate clones, 32 human Chromosome 21 genes, which can be overexpressed in an inducible manner. Each clone was transcriptionally profiled in inducing versus non-inducing conditions. Analysis of the transcriptional response yielded results that were consistent with the perturbed gene's known function. Comparison between mouse ES cells containing the whole human Chromosome 21 (trisomic mouse ES cells) and mouse ES cells overexpressing single human Chromosome 21 genes allowed us to evaluate the contribution of single genes to the trisomic mouse ES cell transcriptome. In addition, for the clones overexpressing the Runx1 gene, we compared the transcriptome changes with the corresponding protein changes by mass spectroscopy analysis. Conclusions We determined that only a subset of genes produces a strong transcriptional response when overexpressed in mouse ES cells and that this effect can be predicted taking into account the basal gene expression level and the protein secondary structure. We showed that the human Chromosome 21-mouse ES cell bank is an important resource, which may be instrumental towards a better understanding of Down syndrome and other human aneuploidy disorders.

  • Chromosome 21: a small land of fascinating disorders with unknown pathophysiology.
    The International journal of developmental biology, 2002
    Co-Authors: Stylianos E Antonarakis, Robert Lyle, Samuel Deutsch, Alexandre Reymond
    Abstract:

    In the year 2000 we celebrated the sequencing of the entire long arm of human Chromosome 21. This achievement now provides unprecedented opportunities to understand the molecular pathophysiology of trisomy 21, elucidate the mechanisms of all monogenic disorders of Chromosome 21, and discover genes and functional sequence variations that predispose to common complex disorders. All of that requires the functional analysis of gene products in model organisms, and the determination of the sequence variation of this Chromosome.

  • Chromosome 21: from sequence to applications.
    Current opinion in genetics & development, 2001
    Co-Authors: Stylianos E Antonarakis
    Abstract:

    Last year we celebrated the sequencing of the entire long arm of human Chromosome 21. This achievement now provides unprecedented opportunities to understand the molecular pathophysiology of trisomy 21, elucidate the mechanisms of all monogenic disorders of Chromosome 21, and discover genes and functional sequence variations that predispose to common complex disorders. All these steps require the functional analysis of gene products and the determination of the sequence variation of this Chromosome.

  • cloning of 559 potential exons of genes of human Chromosome 21 by exon trapping
    Genome Research, 1996
    Co-Authors: Haiming Chen, Roman Chrast, Colette Rossier, Michael A Morris, Maria D Lalioti, Stylianos E Antonarakis
    Abstract:

    Chromosome 21 represents approximately 1% of the human genome, and its long arm has been estimated to contain 600-1000 genes. A dense linkage map and almost complete physical maps based on yeast artificial Chromosomes (YACs) and cosmids have been developed. We have used exon trapping to identify portions of genes from randomly picked Chromosome 21-specific cosmids, to contribute to the creation of the transcription (genic) map of this Chromosome and the cloning of its genes. A total of 559 different sequences were identified after elimination of false-positive clones and repetitive elements. Among these, exons for 13 of the 30 known Chromosome 21 genes have been "trapped." In addition, a considerable number of trapped sequences showed homologies to genes from other species and to human expressed sequence tags (ESTs). One hundred thirty-three trapped sequences were mapped, and every one mapped back to Chromosome 21. We estimate that we have identified portions of up to approximately 40% of all genes on Chromosome 21. The genic map of Chromosome 21 provides a valuable tool for the elucidation of function of the genes and will enhance our understanding of the pathophysiology of Down syndrome and other disorders of Chromosome 21 genes.

  • Duplication and loss of Chromosome 21 in two children with Down syndrome and acute leukemia
    American journal of medical genetics, 1995
    Co-Authors: Peter K. Rogan, Jean-louis Blouin, Pamelyn Close, James R. Seip, Lee Gannutz, Roger L. Ladda, Stylianos E Antonarakis
    Abstract:

    Acute leukemia in Down syndrome (DS) is often associated with additional changes in the number or structure of Chromosome 21. We present two DS patients whose leukemic karyotypes were associated with changes in Chromosome 21 ploidy. Patient 1 developed acute lymphocytic leukemia (type L1); disomy for Chromosome 21 was evident in all blast cells examined. Loss of the paternal Chromosome in the leukemic clone produced maternal uniparental disomy with isodisomy over a 25-cM interval. The second patient had acute monoblastic leukemia (type M5) with tetrasomy 21 in all leukemic cells. DNA polymorphism analysis showed duplicate paternal Chromosomes in the constitutional genotype. The maternal Chromosome was subsequently duplicated in the leukemic clone. The distinct inheritance patterns of Chromosome 21 in the blast cells of these patients would appear to indicate that leukemogenesis occurred by different genetic mechanisms in each individual.

Katheleen Gardiner - One of the best experts on this subject based on the ideXlab platform.

  • the proteins of human Chromosome 21
    American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2006
    Co-Authors: Katheleen Gardiner, Alberto Costa
    Abstract:

    Recent genomic sequence annotation suggests that the long arm of human Chromosome 21 encodes more than 400 genes. Because there is no evidence to exclude any significant segment of 21q from containing genes relevant to the Down syndrome (DS) cognitive phenotype, all genes in this entire set must be considered as candidates. Only a subset, however, is likely to make critical contributions. Determining which these are is both a major focus in biology and a critical step in efficient development of therapeutics. The subtle molecular abnormality in DS, the 50% increase in Chromosome 21 gene expression, presents significant challenges for researchers in detection and quantitation. Another challenge is the current limitation in understanding gene functions and in interpreting biological characteristics. Here, we review information on Chromosome 21-encoded proteins compiled from the literature and from genomics and proteomics databases. For each protein, we summarize their evolutionary conservation, the complexity of their known protein interactions and their level of expression in brain, and discuss the implications and limitations of these data. For a subset, we discuss neurologically relevant phenotypes of mouse models that include knockouts, mutations, or overexpression. Lastly, we highlight a small number of genes for which recent evidence suggests a function in biochemical/cellular pathways that are relevant to cognition. Until knowledge deficits are overcome, we suggest that effective development of gene–phenotype correlations in DS requires a serious and continuous effort to assimilate broad categories of information on Chromosome 21 genes, plus the creation of more versatile mouse models. © 2006 Wiley-Liss, Inc.

  • The proteins of human Chromosome 21.
    American journal of medical genetics. Part C Seminars in medical genetics, 2006
    Co-Authors: Katheleen Gardiner, Alberto C S Costa
    Abstract:

    Recent genomic sequence annotation suggests that the long arm of human Chromosome 21 encodes more than 400 genes. Because there is no evidence to exclude any significant segment of 21 q from containing genes relevant to the Down syndrome (DS) cognitive phenotype, all genes in this entire set must be considered as candidates. Only a subset, however, is likely to make critical contributions. Determining which these are is both a major focus in biology and a critical step in efficient development of therapeutics. The subtle molecular abnormality in DS, the 50% increase in Chromosome 21 gene expression, presents significant challenges for researchers in detection and quantitation. Another challenge is the current limitation in understanding gene functions and in interpreting biological characteristics. Here, we review information on Chromosome 21-encoded proteins compiled from the literature and from genomics and proteomics databases. For each protein, we summarize their evolutionary conservation, the complexity of their known protein interactions and their level of expression in brain, and discuss the implications and limitations of these data. For a subset, we discuss neurologically relevant phenotypes of mouse models that include knockouts, mutations, or overexpression. Lastly, we highlight a small number of genes for which recent evidence suggests a function in biochemical/cellular pathways that are relevant to cognition. Until knowledge deficits are overcome, we suggest that effective development of gene-phenotype correlations in DS requires a serious and continuous effort to assimilate broad categories of information on Chromosome 21 genes, plus the creation of more versatile mouse models.

  • Human Chromosome 21/Down syndrome gene function and pathway database.
    Gene, 2005
    Co-Authors: Oleksii Nikolaienko, Cao Nguyen, Linda S. Crinc, Krzysztof J. Cios, Katheleen Gardiner
    Abstract:

    Down syndrome, trisomy of human Chromosome 21, is the most common genetic cause of intellectual disability. Correlating the increased expression, due to gene dosage, of the >300 genes encoded by Chromosome 21 with specific phenotypic features is a goal that becomes more feasible with the increasing availability of large scale functional, expression and evolutionary data. These data are dispersed among diverse databases, and the variety of formats and locations, plus their often rapid growth, makes access and assimilation a daunting task. To aid the Down syndrome and Chromosome 21 community, and researchers interested in the study of any Chromosome 21 gene or ortholog, we are developing a comprehensive Chromosome 21-specific database with the goals of (i) data consolidation, (ii) accuracy and completeness through expert curation, and (iii) facilitation of novel hypothesis generation. Here we describe the current status of data collection and the immediate future plans for this first human Chromosome-specific database.

  • evolutionary breakpoints on human Chromosome 21
    Genomics, 2001
    Co-Authors: Muriel T Davisson, Lar J Bechtel, Ellen C Akeson, Andrew Fortna, D Slavov, Katheleen Gardiner
    Abstract:

    Segments of the long arm of human Chromosome 21 are conserved, centromere to telomere, in mouse Chromosomes 16, 17, and 10. There have been 28 genes identified in human Chromosome 21 between TMPRSS2, whose orthologue is the most distal gene mapped to mouse Chromosome 16, and PDXK, whose orthologue is the most proximal gene mapped to mouse Chromosome 10. Only 6 of these 28 genes have been mapped in mouse, and all are located on Chromosome 17. To better define the Chromosome 17 segment and the 16 to 17 transition, we used a combination of mouse radiation hybrid panel mapping and physical mapping by mouse:human genomic sequence comparison. We have determined the mouse chromosomal location of an additional 12 genes, predicted the location of 7 more, and defined the endpoints of the mouse Chromosome 17 region. The mouse Chromosome 16/Chromosome 17 evolutionary breakpoint is between human genes ZNF295 and UMODL1, showing there are seven genes in the Chromosome 16 segment distal to Tmprss2. The Chromosome 17/Chromosome 10 breakpoint seems to have involved a duplication of the gene PDXK, which on Chromosome 21 lies immediately distal to the KIAA0179 gene. These data suggest that there may be as few as 21 functional genes in the mouse Chromosome 17 segment. This information is important for defining existing and constructing more complete mouse models of Down syndrome.

  • Molecular analysis and breakpoint definition of a set of human Chromosome 21 somatic cell hybrids.
    Somatic cell and molecular genetics, 1995
    Co-Authors: Sharon L. Graw, Katheleen Gardiner, Karen Hall-johnson, Iris Hart, Anthony Joetham, Katy A. Walton, Deirdre Donaldson, David Patterson
    Abstract:

    Rodent-human somatic cell hybrids containing single human Chromosomes or Chromosome fragments are extremely valuable in physical mapping, marker analysis, and disease mapping. Chromosome 21 has been extensively studied in this fashion, and a single set of hybrids has been utilized in mapping the majority of Chromosome 21 markers. The utility of a set of hybrids depends upon the definition of the human Chromosome content. Recently, Chumakov and coworkers (1) utilized 198 Chromosome 21 markers in the preliminary analysis of YACs spanning Chromosome 21q. We have used these same markers to evaluate the STS content of a set of 27 Chromosome 21 somatic cell hybrids, resulting in the description of the breakpoints at the molecular level, as well as the definition of 35 “bins.” The detailed molecular definition of Chromosome 21 content of the hybrids, in combination with the further analysis of Chromosome 21 YACs (2), has resulted in the most detailed picture of Chromosome 21 to date.

David Patterson - One of the best experts on this subject based on the ideXlab platform.

  • Molecular analysis and breakpoint definition of a set of human Chromosome 21 somatic cell hybrids.
    Somatic cell and molecular genetics, 1995
    Co-Authors: Sharon L. Graw, Katheleen Gardiner, Karen Hall-johnson, Iris Hart, Anthony Joetham, Katy A. Walton, Deirdre Donaldson, David Patterson
    Abstract:

    Rodent-human somatic cell hybrids containing single human Chromosomes or Chromosome fragments are extremely valuable in physical mapping, marker analysis, and disease mapping. Chromosome 21 has been extensively studied in this fashion, and a single set of hybrids has been utilized in mapping the majority of Chromosome 21 markers. The utility of a set of hybrids depends upon the definition of the human Chromosome content. Recently, Chumakov and coworkers (1) utilized 198 Chromosome 21 markers in the preliminary analysis of YACs spanning Chromosome 21q. We have used these same markers to evaluate the STS content of a set of 27 Chromosome 21 somatic cell hybrids, resulting in the description of the breakpoints at the molecular level, as well as the definition of 35 “bins.” The detailed molecular definition of Chromosome 21 content of the hybrids, in combination with the further analysis of Chromosome 21 YACs (2), has resulted in the most detailed picture of Chromosome 21 to date.

  • Five new microsatellite polymorphisms at the q21 region of human Chromosome 21
    Human genetics, 1995
    Co-Authors: Assumpció Bosch, David Patterson, Stefan Wiemann, Jordi Guimerà, Wilhelm Ansorge, Xavier Estivill
    Abstract:

    Five clones, containing polymorphic CA-repeat sequences, have been isolated from a specific human Chromosome 21 phage library and have been localised to band q21 of Chromosome 21 using a somatic cell hybrid panel. These highly repetitive sequences (D21S1263, D21S1264, D21S1415, D21S1417 and D21S1420) have been characterised in the CEPH reference parents and have heterozygosities ranging from 0.30 to 0.81 and an average polymorphism information content (PIC) of 0.62. The relative order of these markers, based on the somatic cell hybrid panel, is cen-D21S1417, D21S1420-D21S1263, D21S1415-D21S1264-tel. The most polymorphic marker (D21S1264) has been included in the Chromosome 21 genetic map. They have also been localised in the CEPH/ Genethon YAC panel, providing a refined localisation of these polymorphic sequences. These five CA-repeat markers should provide a better characterisation of the q21 region of Chromosome 21.

  • A verified minimal YAC contig for human Chromosome 21
    American Journal of Human Genetics, 1994
    Co-Authors: Sharon L. Graw, David Patterson
    Abstract:

    The goal of this project is the construction of a verified YAC contig of the complete long arm of human Chromosome 21 utilizing YACs from the CEPH and St. Louis libraries. The YACs in this contig have been analyzed for size by PFGE, tested for chimerism by FISH or end-cloning, and verified for STS content by PCR. This last analysis has revealed a number of cases of conflict with the published STS order. To establish correct order, we have utilized STS content analysis of somatic cell hybrids containing portions of Chromosome 21. Additional problems being addressed include completeness of coverage and possible deletions or gaps. Questions of completeness of the CEPH 810 YAC set arose after screening with 57 independently derived probes failed to identify clones for 11 (19%). Ten of the 11, however, do detect Chromosome 21 cosmids when used to screen Lawrence Livermore library LL21NC02`G,` a cosmid library constructed from flow-sorted Chromosomes 21. Remaining gaps in the contig are being closed by several methods. These include YAC fingerprinting and conversion of YACs to cosmids. In addition, we are establishing the overlap between the physical NotI map and the YAC contig by testing YACs for NotI sites and screeningmore » the YACs in the contig for the presence of NotI-linking clones.« less

  • Isolation and refined regional mapping of expressed sequences from human Chromosome 21.
    Genomics, 1994
    Co-Authors: Fa-ten Kao, Suhong Tong, Sankhavaram R. Patanjali, Sherman M. Weissman, David Patterson
    Abstract:

    To increase candidate genes from human Chromosome 21 for the analysis of Down syndrome and other genetic diseases localized on this Chromosome, we have isolated and studied 9 cDNA clones encoded by Chromosome 21. For isolating cDNAs, single-copy microclones from a Chromosome 21 microdissection library were used in direct screening of various cDNA libraries. Seven of the cDNA clones have been regionally mapped on Chromosome 21 using a comprehensive hybrid mapping panel comprising 24 cell hybrids that divide the Chromosome into 33 subregions. These cDNA clones with refined mapping positions should be useful for identification and cloning of genes responsible for the specific component phenotypes of Down syndrome and other diseases on Chromosome 21, including progressive myoclonus epilepsy in 21q22.3.

  • Physical mapping of Chromosome 21.
    Progress in clinical and biological research, 1993
    Co-Authors: David Patterson, Katheleen Gardiner, Rahmani Z, Donaldson D, Carol Jones
    Abstract:

    Chromosome 21, the smallest human Chromosome, has been the subject of intense study because it is the Chromosome which, when present in an extra copy, leads to Down Syndrome. Moreover, there are genes important for several human genetic disorders on this Chromosome, and a significant number of individuals with aneuploidies of regions of the Chromosome have been identified. A high fidelity, high resolution physical map of Chromosome 21 will be of immense value in generating an accurate genotype/phenotype map of the Chromosome and in identifying and isolating genes on the Chromosome which may be responsible for various human genetic disorders. Here we describe the current status of our attempts to create such a map. This includes attempts to integrate various physical mapping approaches. Progress towards construction of a minimal set of yeast artificial Chromosomes (YACs) spanning the Chromosome is described.

Roser Gonzàlez-duarte - One of the best experts on this subject based on the ideXlab platform.

  • Molecular characterisation of partial Chromosome 21 aneuploidies by fluorescent PCR.
    Journal of medical genetics, 1999
    Co-Authors: Rebeca Valero, Gemma Marfany, Rosario Gil-benso, Maria De Los Angeles Ibáñez, Isidora López-pajares, Félix Prieto, Gaspar Rullan, Enric Sarret, Roser Gonzàlez-duarte
    Abstract:

    Although trisomy of Chromosome 21 is the most prevalent human genetic disorder, data from partial 21 aneuploidies are very scanty. Eight different partial aneuploidies for Chromosome 21 were characterised by fluorescence quantitative PCR. Allelic dosage analysis was performed for each patient using 25 CHLC STRs covering the entire q arm. The length of the corresponding trisomies and monosomies was ascertained for five partial trisomics and three partial monosomics. All trisomic patients carried unbalanced translocations involving Chromosome 21, whereas one of the monosomic patients bore a ring Chromosome 21 and another showed an interstitial deletion of Chromosome 21. The chromosomal breakpoints of two partial trisomy patients could be clearly delimited. However, the other three trisomies involved most of the 21 q arm as three allelic doses were detected for each marker. Although these latter patients do not show all the features of Down syndrome, genotype/phenotype correlations agree with previously reported data. The chromosomal breakpoints observed in two partially monosomic patients helped further to define the region involved in different phenotypic features associated with Chromosome 21 monosomy. Telomeric material loss was also detected in a patient bearing a ring 21 Chromosome. The parental origin of the aneuploidy was assigned for each case, which allowed us to conclude that two of the monosomic cases originated from de novo chromosomal rearrangements. There was no correlation with parental sex in contrast to trisomic patients originating from meiotic non-disjunction.

Roland Berger - One of the best experts on this subject based on the ideXlab platform.

  • Chromosome 21 abnormalities with AML1 amplification in acute lymphoblastic leukemia.
    Genes chromosomes & cancer, 2001
    Co-Authors: Maryvonne Le Coniat, Florence Nguyen Khac, Marie-thérèse Daniel, Olivier Bernard, Roland Berger
    Abstract:

    Fluorescence in situ hybridization (FISH) studies were performed in three cases of acute lymphoblastic leukemia (ALL) with marker Chromosomes to analyze the contribution of Chromosome 21 in these markers. FISH with a Chromosome 21 painting probe confirmed that Chromosome 21 was involved in all three cases. FISH with YAC probes showed that the number of extra copies varied according to their location on Chromosome 21. Attention was focused on the AML1 gene, which was present as five copies in most of the cells exhibiting the marker Chromosomes. As controls, 11 cases of childhood ALL were studied with PAC probes covering AML1. The results agreed with the banded karyotypes in 10 patients. FISH uncovered a clone with four copies of AML1 which were only observed by FISH analysis of interphase nuclei in one patient. No point mutation was detected in exons 3–5, encoding the runt domain of AML1, in the three cases, suggesting an oncogenic role of wild-type AML1 amplification. © 2001 Wiley-Liss, Inc.

  • Acute lymphoblastic leukemia and Chromosome 21
    Cancer genetics and cytogenetics, 1997
    Co-Authors: Roland Berger
    Abstract:

    A short review of Chromosome 21 abnormalities in acute lymphoblastic leukemia (ALL) is presented. Trisomy and polysomy 21 are nonrandom anomalies that are frequently observed in ALL. Their occurrence, although not specific, as well as the high incidence of acute leukemia in subjects with constitutional trisomy 21, suggests that Chromosome 21 plays a particular role in leukemogenesis. More specific to ALL, t(12;21)(p13;q22), resulting in a fusion TEL-AML1, gene has recently been shown to be the most frequent translocation in childhood B-cell lineage ALL (20-30% of cases). In addition, the importance of analysis of marker Chromosomes with fluorescence in situ hybridization (FISH) techniques is underscored as partial amplifications or rearrangements of Chromosome 21 may be implicated.

  • Partial Chromosome 21 amplification in a child with acute lymphoblastic leukemia
    Genes chromosomes & cancer, 1995
    Co-Authors: Maryvonne Le Coniat, Serge Romana, Roland Berger
    Abstract:

    Monosomy 21 and metacentric markers corresponding in size to Chromosomes 8 to 12 were found as the only clonal chromosomal changes in a child with acute lymphoblastic leukemia (ALL). Chromosome painting with a whole Chromosome 21-specific probe showed that the marker originated from Chromosome 21. Fluorescence in situ hybridization with yeast artificial Chromosome (YAC) probes to Chromosome 21 showed genomic amplification with two, four, or more copies of the probed DNA sequences present on the marker. The most amplified regions of Chromosome 21 were centromeric and telomeric to the Down's syndrome region. This observation supports the notion that amplification of only parts of Chromosome 21 may be important in the leukemogenic process in spite of the high incidence of complete trisomy 21 in ALL.