Severe psychomotor retardation in a boy with a supernumerary derivative chromosome resulting in partial trisomy 21 and partial trisomy 7p

We report on a 12-year-old boy with a supernumerary chromosome der(21)t(7; 21)(p21; q21.3)mat, resulting in a partial trisomy 21 and a partial trisomy 7p. The patient has a severe psychomotor retardation. Although he has most of chromosome 21 in three copies, he does not have a phenotype of Down syndrome (DS). In addition to cytogenetic analysis, molecular analysis confirmed that the "DS critical region" on chromosome 21 (21q22) is not present in three copies, since the breakpoint of the partial trisomy 21 was found to be located distal to the marker locus D21S145 but proximal to D21S226. The patient's severe mental retardation is probably due to the small telomeric 7p trisomy, having the breakpoint between markers D7S507 and D7S488. In comparison with previously published cases of partial trisomy 7p, the phenotype of this patient indicates that there is a region around the distal part of band 7p21 that in three copies might contribute to many of the facial features common to patients with partial trisomy 7p.     

Altered placental morphology associated with murine trisomy 16 and murine trisomy 19

The morphology of placentas from trisomy 16 and trisomy 19 mouse conceptuses aged 12 to 18 gestational days was studied at the light microscopic level. Comparisons were made with placentas from normal littermate animals. Trisomy 16 placentas showed marked changes from normal: 1) the junctional zone showed little indication of normal morphologic differentiation throughout gestation; 2) clusters of germinal trophoblast cells persisted in the labyrinth throughout gestation, whereas these cells disappeared by gestational day 16 in the normal littermate placentas; 3) the labyrinth was reduced in size in the trisomic placentas, and the differentiation of the interhemal membranes was delayed. The size of the labyrinths from trisomy 19 placentas appeared to be decreased, but otherwise the placentas appeared to have normal morphology. These observations and others from the literature show that placental development is affected by the presence of a trisomic genome, and that different trisomies influence the development of the placenta differently. For trisomy 16, we propose that the striking changes of the junctional zone may be associated with the trisomy 16-related gene dosage effect for alpha- and beta-interferon cell surface receptors. Because of the homology for this and other genes on mouse chromosome 16 with genes on human chromosome 21, findings related to the altered development of the trisomy 16 mouse may be relevant to understanding some of the phenotypic variations associated with human trisomy 21, the Down syndrome.     

Pure partial trisomy of the short arm of chromosome 5

Summary We describe a male infant with multiple dysmorphic features who is trisomic for chromosome segment 5p13.325p14.2 as a result of recombination aneusomy. His father is a balanced carrier of an inverted insertion of this chromosome segment. The clinical features of this patient are compared with those of other patients with isolated partial 5p trisomy reported in the literature.     

Molecular-cytogenetic identification of partial trisomy of a short arm of chromosome 8

We present de novo diagnosed case of partial trisomy of short arm of chromosome 8 with psyhomotoric delay and microanomalies. Inverted duplication of short arm of chromosome 8 was identified using molecular-cytogenetic method. This case is compared with literature data on the same cases. The further intensive study of such cases is necessary to delineate this chromosomal syndrome     

Effect of a partial trisomy in the mouse upon cellular and nuclear RNA

In a previous paper (Rake and Edwards, 1987) it was shown that the majority of the chromatin from trisomic mouse cells has nucleosomes with a smaller repeat length of DNA than the nucleosome repeat length of normal cells. Here it is shown that the RNA content of the total cell and of the nuclei is the same in all tissues studied, in both normal and trisomic cells. However, the amount per unit time or rate of RNA synthesis is depressed in the trisomic liver and brain nuclei. The depression of RNA synthesis could not be specified to the small trisomic section of the chromatin but instead must reflect the overall nuclear activity. These results, along with those of Devlinet al. (1988), indicate that the trisomic condition alters a substantial part of nuclear organization and activity, not just the small trisomic part.     

Altered structure of HLA class I heavy chains associated with mouse beta-2 microglobulin

The serological reactivities of HLA-A3, -B7, and -CW3 heavy chains associated with either mouse, bovine, or human beta-2 microglobulin ( ₂m) and expressed on the surface of transfected mouse fibroblasts were analyzed. All reactivities associated with one cluster (defined by monoclonal antibody W6/32) of antigenic determinants expressed by these HLA class I molecules were lost, or profoundly reduced, after each heavy chain associated with mouse ₂-m. Expression by the transfected fibroblasts of the HLA-A3, -B7, and -CW3 heavy chains in association with human ₂m restores these reactivities. Since most of the amino acid differences between mouse and human ₂m probably correspond to externally oriented hydrophilic residues, these results suggest that critical interactions in the three-dimensional structure of HLA class I molecules occur between the light chain and the first two external domains of the class I heavy chains, to which some of the altered reactivities have been mapped.     

A satellited Yq chromosome associated with trisomy 21 and an inversion of chromosome 9

Summary A case of satellited Yq, inverted 9 and trisomy 21 is described. The clinical features are typical of those found in Down's syndrome.     

Familial transmission of a 3q;22p translocation, with partial trisomy of chromosome 3 in the propositus

A family, carrying a balanced 3q;22p translocation, was detected through a propositus who showed multiple congenital malformations. As there are no previous references of similar cases where identification techniques were performed, the authors present this material for consideration in the delineation of clinical syndromes associated with specific chromosomal anomalies.     

A protease activity is associated with testicular chromatin of the mouse

A protease activity associated with the micrococcal nuclease-solubilized chromatin from mouse seminiferous tubules has been characterized. Proteolysis of histone H1 and core histones is stimulated in the presence of 3 M urea. The pH optimum of this protease is between pH 8 and 9, and the activity is not inhibited by trypsin or chymotrypsin-active site inhibitors. Leupeptin is an effective inhibitor of the protease at low concentrations. Soluble chromatin from neonatal and prepubertal mice lacks this proteolytic activity until three to four weeks after birth. That the protease activity is localized in the dinucleosomes and higher oligomers but is lacking in mononucleosome populations suggests its association with the linker DNA. Rat testis-soluble chromatin apparently lacks such a protease activity. The developmental expression of this protease and its in situ localization are consistent with a role in histone displacement during mouse spermiogenesis.     

Complete or partial trisomy for the long arm of chromosome 1 in patients with various hematologic malignancies

This study contains data obtained from a cytogenetic investigation of six patients with acute and chronic leukaemia. The karyotypes of bone marrow or blood cells of these patients showed a partial or complete trisomy for the long arm of chromosome 1. Three observations revealed a pronounced resistance of cell clones with 1q+ towards cytostatic therapy, and a comparatively short life span of patients after detection of 1q+. The importance of these changes for the role of some chromosomes and chromosome loci in leukaemogenesis is discussed.     

Altered DNA methylation in leukocytes with trisomy 21

The primary abnormality in Down syndrome (DS), trisomy 21, is well known; but how this chromosomal gain produces the complex DS phenotype, including immune system defects, is not well understood. We profiled DNA methylation in total peripheral blood leukocytes (PBL) and T-lymphocytes from adults with DS and normal controls and found gene-specific abnormalities of CpG methylation in DS, with many of the differentially methylated genes having known or predicted roles in lymphocyte development and function. Validation of the microarray data by bisulfite sequencing and methylation-sensitive Pyrosequencing (MS-Pyroseq) confirmed strong differences in methylation (p<0.0001) for each of 8 genes tested: TMEM131, TCF7, CD3Z/CD247, SH3BP2, EIF4E, PLD6, SUMO3, and CPT1B, in DS versus control PBL. In addition, we validated differential methylation of NOD2/CARD15 by bisulfite sequencing in DS versus control T-cells. The differentially methylated genes were found on various autosomes, with no enrichment on chromosome 21. Differences in methylation were generally stable in a given individual, remained significant after adjusting for age, and were not due to altered cell counts. Some but not all of the differentially methylated genes showed different mean mRNA expression in DS versus control PBL; and the altered expression of 5 of these genes, TMEM131, TCF7, CD3Z, NOD2, and NPDC1, was recapitulated by exposing normal lymphocytes to the demethylating drug 5-aza-2'deoxycytidine (5aza-dC) plus mitogens. We conclude that altered gene-specific DNA methylation is a recurrent and functionally relevant downstream response to trisomy 21 in human cells.     

Evidence for a subunit structure of chromatin in mouse myeloma cells

If micrococcal nuclease is allowed to digest chromatin as it exists inside intact nuclei isolated from mouse myeloma tissue culture cells, more than 60% of the DNA can be isolated as a homogeneous fragment on a sucrose gradient. Analytical ultracentrifugation indicates that the protected DNA is native, unnicked, and about 140 +/- 10 base pairs long. After less extensive nuclease digestion, the protected DNA migrates in gels in lengths which are integral multiples of this 140 base pair "monomer" band. A submonomer band, 105 "/- 10 base pairs long, can also be detected. Similar digestion patterns were obtained by two different nuclear isolation procedures and even when intact cells were gently lysed directly in the digestion medium. These results confirm and extend the chromatin digestion studies of previous investigators and provide support for a subunit model for eukaryotic chromatin. The single strand specific S1 nuclease did not digest intranuclear chromatin under the conditions used.     

Altered chromatin structure of cerebral nuclei in experimental diabetes mellitus.

To determine whether diabetes alters chromatin structure in vivo, micrococcal nuclease digestion kinetics were analyzed in cerebral cortical and hepatic nuclei of streptozotocin-induced diabetic rats. Cerebral nuclei of diabetic rats maintained for 6 weeks were less susceptible to micrococcal nuclease digestion compared with control rats. Insulin treatment reversed diabetes-related changes in nuclease digestion kinetics. There were no changes in the kinetics of digestion in hepatic nuclei. The reduced digestibility of cerebral DNA in diabetes could not be attributed to altered DNA fluorescence spectra, or altered distribution of most abundant chromatin proteins that were either solubilized or that remained insoluble immediately following nuclease digestion. It is concluded that chronic, uncontrolled hyperglycemia can alter chromatin structure of some tissues in vivo, and this change is probably related to subtle alterations in DNA-protein interactions.     

Precocious puberty associated with partial trisomy 18q and monosomy 11q

We report a 10-years-old female patient with a partial trisomy 18q and monosomy 11q due to a maternal translocation. The phenotype of our proband is partially common with Jacobsen syndrome and duplication 18q but she has also some atypical anomalies such as precocious puberty, a retinal albinism and hypermetropia. Based on cytogenetics and FISH analysis, the karyotype of the proband was 46,XX,der(11)t(11;18)(q24;q13). To the best of our knowledge, this is the first report of precocious puberty associated with either dup(18q) or del(11q) syndromes.     

Interleukin-6 repression is associated with a distinctive chromatin structure of the gene.

Expression of the interleukin-6 (IL-6) gene is usually tightly controlled and may be induced in specific tissues only after treatment with appropriate stimuli. The molecular mechanisms responsible for IL-6 gene repression in specific tissues or cell lines remain poorly defined. In order to address this question we have studied two human breast carcinoma cell lines, MDA-MB-231, in which the IL-6 gene is expressed, and MCF-7, in which it is not. The promoter region of the IL-6 gene was analysed in both cell lines with reference to two different parameters: (i) DNase I hypersensitivity; (ii) the in vivo pattern of DNA-protein interactions. We show herein that the mechanism responsible for silencing IL-6 gene expression in MCF-7 cells most probably involves a modification of chromatin structure, as suggested by a decreased sensitivity of the IL-6 promoter to DNase I relative to the IL-6-expressing cell line MDA-MB-231. Moreover, we show that a 'closed' nucleosomal structure in MCF-7 cells does not inhibit the binding of nuclear proteins to IL-6 gene regulatory sequences in vivo. We suggest, therefore, that, in non-expressing cells, local chromatin remodelling at the proximal promoter is inhibited by negative regulators, as suggested by two specific hallmarks of nuclear factor binding that are not observed in expressing cells: an additional in vivo footprint spanning positions -135/-119 and an additional DNase I hypersensitive site far upstream, around position -1400. Furthermore, a specific factor binding in vitro to the -140/-116 region of the IL-6 promoter is found in MCF-7 cells.     

Altered biological activity associated with C-terminal modifications of IL-7

Interleukin 7 (IL-7) is a pleiotropic cytokine which plays a role in both T and B cell function as well as in establishment and maintenance of immunological barriers in epithelial tissues. The heterodimeric IL-7 receptor (IL-7R) consists of the p76 IL-7Ralpha subunit and the p64 common gamma (gammac) subunit. Ligand-binding induces signal transduction through tyrosine phosphorylation of the janus (Jak) and src-related kinases as well as by activation of phosphatidinositol-3 kinase (P13-kinase). In an effort to further define the requirements for ligand-receptor interactions and to subsequently develop candidate receptor binding antagonists with selective biological activities, we examined a series of IL-7 mutants in which the carboxy terminal hydrophobic residues were substituted with aliphatic amino acids. In this study we describe abrogation of IL-7 driven proliferation and attenuated phosphotyrosine signaling by IL-7(143) (Trp-Ala) and IL-7(143) (Trp-His) in IL-7R expressing T and B leukemia cells. Decreased phosphorylation of Jak3 kinase by IL-7W143A, IL-7W143P and IL-7W143H suggest that alterations in this region of the carboxyterminal region of IL-7 affects its interaction with the gammac subunit of the IL-7R.