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At least 1,063 records · Page 59Linked to original sources
PubMed1989

Cytogenetic effects of tobacco smoke exposure among involuntary smokers.

Tobacco smoke is highly genotoxic and produces chromosomal damage in several experimental systems. Active smokers have been shown to have an increased prevalence of somatic chromosome damage in their peripheral blood lymphocytes: this is seen in most cases as an increased sister-chromatid exchange (SCE) frequency and often also as increased structural chromosome aberrations (CAs). Among passive smokers, in association with exposure to environmental tobacco smoke, no such induction of chromosomal damage has been documented. In the present paper we report negative results on induction of chromosomal damage in 2 separate groups of intensive involuntary exposure to tobacco smoke, non-smoking restaurant personnel and newborn children of smoking mothers. While significant exposure in these groups is clearly seen in biochemical intake markers, e.g. cotinine and thiocyanate values in plasma, the conventional cytogenetic parameters, structural chromosome aberrations and sister-chromatid exchanges, are unable to detect the low exposures of involuntary smokers.

Cells, Cultured↗
PubMed2004

Chromosome analysis of mouse one-cell androgenones derived from a sperm nucleus exposed to topoisomerase II inhibitors at pre- and post-fertilization stages.

Mouse spermatozoa and androgenetic one-cell embryos (androgenones) at various developmental stages were exposed to etoposide (1 microM), a topoisomerase II (topo II) poison, or to either of two catalytic inhibitors: ICRF-193 (10 microM) or merbarone (50 microM), for 2 h in order to study the clastogenic effects of these drugs on remodeled sperm chromatin. None of the drugs induced structural chromosome aberrations in condensed chromatin of spermatozoa. However, etoposide and merbarone exerted strong clastogenic actions on remodeled chromatin of androgenones. Expanding chromatin was most sensitive to both of these drugs at the time of pronuclear formation, as nearly 100% of androgenones exposed at this stage displayed structural chromosome aberrations. ICRF-193 did not affect sperm chromatin at all remodeling stages. A majority of the aberrations induced by etoposide and merbarone were of the chromosome-type. Chromosome exchanges, including translocation, dicentric, and ring chromosomes, preferentially appeared following exposure at the early stages of chromatin remodeling. Thus, despite their different modes of topo II inhibition, etoposide and merbarone showed similar clastogenic actions on remodeled sperm chromatin. These results suggest that the formation of transient DNA cleavage, mediated by ooplasmic topo II, accompanies the remodeling. The present findings provide insight into the mechanisms by which structural aberrations are generated in paternal chromosomes.

Animals↗
PubMed1986

The chromosomal gene structure and two mRNAs for human granulocyte colony-stimulating factor.

Two different cDNAs for human granulocyte colony-stimulating factor (G-CSF) were isolated from a cDNA library constructed with mRNA prepared from human squamous carcinoma cells, which produce G-CSF constitutively. The nucleotide sequence analysis of both cDNAs indicated that two polypeptides coded by these cDNAs are different at one position where three amino acids are deleted/inserted. When the two cDNAs were introduced into monkey COS cells under the SV40 early promoter, both of them produced proteins having authentic G-CSF activity and some difference in the specific activity was suggested. A human gene library was then screened with the G-CSF cDNA and the DNA fragment containing the G-CSF chromosomal gene was characterized by the nucleotide sequence analysis. The human G-CSF gene is interrupted by four introns and a comparison of the structures of the two G-CSF cDNAs with that of the chromosomal gene indicated that the two mRNAs are generated by alternative use of two 5' splice donor sequences in the second intron of the G-CSF gene. When the G-CSF chromosomal gene was expressed in monkey COS cells by using the SV40 enhancer two mRNAs were detected by S1 mapping analysis.

Amino Acid Sequence↗
PubMed1997

Genomic structure and chromosomal localization of human uroguanylin.

Uroguanylin, a member of the guanylin peptide family, is a novel peptide regulator in intestinal salt and water transport. We isolated the gene for uroguanylin from a human genomic library and determined its structure. This gene consists of three exons and two introns within an overall length of 2.5 kb. The 5' flanking region has TATA and CAAT boxes. The gene also has multiple binding sites for promoter-specific transcription factor, activator protein-1, and activator protein-2, and a cAMP-regulated enhancer element. Fluorescence in situ hybridization showed the uroguanylin gene at human chromosome 1p33-p34. RNA blot analysis showed that human uroguanylin mRNA is expressed in the gastric fundus and pylorus as well as in the intestine.

Amino Acid Sequence↗
PubMed1996

Genomic structure and chromosomal assignment of the mouse Ku70 gene.

DNA-dependent protein kinase (DNA-PK) consists of three polypeptide subunits: Ku70, Ku80, and the DNA-PK catalytic subunit (DNA-PKcs). Mammalian mutants deficient in either Ku80 or DNA-PKcs function have been shown to be lacking in DNA double-strand break repair and V(D)J recombination, respectively. The precise role of the Ku70 gene in this process has not yet been determined, in part because no cell lines, animals, or human diseases involved with deficiencies in this gene have yet been identified. Both the human and the mouse Ku70 cDNAs have been cloned, and the human gene has been mapped to chromosome 22q13. The original mouse cDNA clones, however, lacked a complete 5'-region, and none of the mammalian Ku70 genomic sequences have been characterized. This report contains an analysis of the 5'-region of the mouse cDNA sequence, a characterization of the mouse Ku70 genomic structure, and fluorescence in situ hybridization data that map the mouse gene to chromosome 15. The deduced amino acid sequence of the mouse gene consists of 608 amino acids compared to 609 for the human gene. The genomic sequence is 24 kb and consists of 13 exons, including an untranslated first exon. Sequences from the upstream region of exon 1 revealed four consensus GC box sequences and a strong transcription initiation site at a reasonable location. The assignment of the mouse Ku70 gene to chromosome 15 is consistent with the syntenic relationship of this gene in human (chromosome 22q13) and mouse and adds to the comparative mapping data for the genes involved in the SCID phenotype.

Animals↗
PubMed1991

CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location.

CD28, initially detected on human T lymphocytes with the help of antibodies, and CTLA-4, obtained by reverse genetics through its preferential expression in mouse activated T cells, are both single-V domain members of the Ig superfamily. Early work showed a relationship between these two molecules, which we wished to further document, in particular because of the growing realization of the functional importance of CD28 in some T cell activation pathways. Isolation and analysis of the mouse CTLA-4 gene and further analysis of the human CTLA-4 gene showed that both of these and the human CD28 gene share the same overall intron/exon organization. The nucleic acid sequence homology of the exons was found to extend across both molecules and species, whereas the 5' and 3' flanking regions exhibited homology across species but not between molecules. Message expression of human CTLA-4 was only detected in activated T cells and, thus, shares with that of mouse CTLA-4 and of mouse and human CD28 a lymphoid tissue distribution, although apparently broader for the latter. Two main human CTLA-4 transcripts of about 1.8 and 0.8 kb were detected, the smaller of which may derive, as reported for human CD28, from the use of an alternate degenerated polyadenylation signal sequence. The nucleic acid sequence data allowed a direct comparison of the four putative complete protein sequences of CD28 and CTLA-4 in the mouse and the human, showing striking homologies, especially in some stretches (such as a MYPPPY hexamer in the hinge region) conserved across molecules and across species. The mouse CD28 gene was localized to chromosome 1 band C by in situ hybridization with three different radioactive probes, indicating, together with previous data, that the CD28 and CTLA-4 genes map to the same chromosomal region in both the mouse and the human. Thus, CD28 and CTLA-4 were found to be strikingly similar in most respects, in terms of structure, sequence, expression, and gene location, furthermore in two species, strongly suggesting that their genes are the direct products of a duplication event and raising the possibility of functional homologies between the corresponding proteins.

Abatacept↗
PubMed1997

Genetic structure and chromosomal mapping of MyD88.

The myeloid differentiation (MyD) marker MyD88 was initially characterized as a primary response gene, upregulated in mouse M1 myeloleukemic cells in response to differentiation induced by interleukin-6. Subsequent analysis revealed that MyD88 possesses a unique modular structure, which consists of an N-terminal "death domain," similar to the intracellular segments of TNF receptor 1 and Fas, and a C-terminal region related to the cytoplasmic domains of the Drosophila morphogen Toll and vertebrate interleukin-1 receptors. In this report we describe the cloning and gene structure of mouse MyD88. The complete coding sequence of mouse MyD88 spans five exons, with the first exon encoding the complete death domain. Zooblot analysis revealed that MyD88 is an evolutionarily conserved gene. MyD88 was localized to the distal region of mouse chromosome 9 by interspecific backcross mapping. The human homolog (hMyD88) was mapped to chromosome 3p22-p21.3 by PCR analysis of a human chromosome 3 somatic cell hybrid mapping panel. Northern blot analysis revealed widespread expression of MyD88 in many adult mouse tissues, and RT-PCR studies detected MyD88 mRNA in T and B cell lines and differentiating embryonic stem cells. The broad expression pattern demonstrates that mouse MyD88 expression is not restricted to cells of myeloid lineage as was originally believed.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Structure and chromosomal localization of the RAE28/HPH1 gene, a human homologue of the polyhomeotic gene.

The Polycomb group of (Pc-G) genes and trithorax group of genes are known to play a crucial role in the maintenance of the transcriptional repression state of Hox genes, probably through modification of the chromatin configuration. The rae28/mph1 gene is a mammalian homologue of the Drosophila polyhomeotic gene, which belongs to the Pc-G genes. As reported previously, we established mice deficient in the rae28/mph1 gene and showed that these homozygous animals displayed the developmental defects compatible with a human congenital disorder, CATCH22 syndrome. In this study we analyzed the structural organization of the human counterpart of the rae28/mph1 gene (RAE28/HPH1) and its processed pseudogene (psiPH), which are located on, respectively, human chromosome 12p13 and 12q13. The HPH1 gene consists of 15 exons spanning approximately 26 kb and its structural organization is well conserved between mouse and human. These genetic information of the RAE28/HPH1 gene may provide an important clue for further examination of its involvement in human congenital disorders related to CATCH22 syndrome.

Animals↗
PubMed1999

Structure and chromosome mapping of the human SIX4 and murine Six4 genes.

Six4, a member of the homeobox gene subfamily (Six), is expressed in a developmentally regulated fashion, and supposed to be involved in embryogenesis. We cloned the human SIX4 and murine Six4 genomic DNAs and determined their structures. The structure, including the 5' upstream region of both genes, was well conserved suggesting the conserved function and regulation of these genes. Human SIX4 was mapped to chromosome 14q23.

Amino Acid Sequence↗
PubMed1995

Structure and chromosomal localization of the mouse neurocan gene.

Cosmid clones containing the mouse neurocan gene were isolated from a genomic library using rat neurocan cDNA fragments as probe. The murine gene has a size of approximately 25 kb and contains the coding sequence for the mRNA on 15 exons. The exon-intron structure reflected the structural organization of neurocan, which is a multidomain protein belonging to the aggrecan/versican proteoglycan family. All introns between conserved modular protein domains are phase I introns. Primer extension experiments indicate a transcriptional start point 28 bases downstream of a consensus TATA sequence. Further analysis of 1 kb of 5' flanking sequence revealed in addition to AP1, AP2, and SP1 consensus binding sites multiple E-box elements and a glucocorticoid responsive element. Single-strand conformation polymorphism was used to map neurocan to chromosome 8 between the microsatellite markers D8Mit29 and D8Mit78. Among mouse mutants that have been mapped around this region are the three allelic neurological diseases tottering, leaner, and rolling. The multidomain structure and the preferential expression of neurocan in the brain suggest a potential involvement in these diseases.

Animals↗
PubMed1995

Nonrandom chromosome breakpoints at Xq26 and 2q33 characterize cemento-ossifying fibromas of the orbit.

BACKGROUND: Cytogenetic reports of histologically benign fibroosseous lesions are rare, with only nine previously reported cases. None of these previous studies revealed consistent numerical or structural chromosome aberrations, and to the authors' knowledge, no karyotypic abnormalities in cemento-ossifying fibromas of the orbit have been reported. METHODS: Short term in situ culture and Giesma-band chromosome methods were used to analyze three cementifying fibromas of the orbit: one from a 13-year-old African American male, one from a 14-year-old Hispanic male, and one from a 17-year-old white male. RESULTS: Cytogenetic findings in these three cases revealed the presence of identical chromosomal breakpoints occurring in all three tumors at bands Xq26 and 2q33. Two of the tumors showed an identical t(X;2)(q26;q33) reciprocal translocation as the sole abnormality. The third tumor revealed an interstitial insertion of bands 2q24.2q33 into Xq26 as the sole abnormality. CONCLUSIONS: The authors described new nonrandom breakpoints in fibroosseous lesions of the orbit, which can result from at least two different types of structural chromosomal aberrations. The identification of recurring breakpoints at Xq26 and 2q33 provides a new cytogenetic tumor marker for the identification of this tumor subtype. The sublocalization of breakpoints in this tumor should provide important information for the precise localization and characterization of genes involved in the histiogenesis of these lesions.

Adolescent↗
PubMed2003

Assessing the role of the T cell receptor beta gene enhancer in regulating coding joint formation during V(D)J recombination.

To assess the role of the T cell receptor (TCR) beta gene enhancer (Ebeta) in regulating the processing of VDJ recombinase-generated coding ends, we assayed TCRbeta rearrangement of Ebeta-deleted (DeltaEbeta) thymocytes in which cell death is inhibited via expression of a Bcl-2 transgene. Compared with DeltaEbeta, DeltaEbeta Bcl-2 thymocytes show a small accumulation of TCRbeta standard recombination products, including coding ends, that involves the proximal Dbeta-Jbeta and Vbeta14 loci but not the distal 5' Vbeta genes. These effects are detectable in double negative pro-T cells, predominate in double positive pre-T cells, and correlate with regional changes in chromosomal structure during double negative-to-double positive differentiation. We propose that Ebeta, by driving long range nucleoprotein interactions and the control of locus expression and chromatin structure, indirectly contributes to the stabilization of coding ends within the recombination processing complexes. The results also illustrate Ebeta-dependent and -independent changes in chromosomal structure, suggesting distinct modes of regulation of TCRbeta allelic exclusion depending on the position within the locus.

Alleles↗
PubMed2004

Reproductive functions of the ageing male.

Delayed childbearing is a common phenomenon in industrialized countries. This review focuses on age-associated alterations of male fertility and genetic risks. Semen volume, sperm motility and sperm morphology decrease with age, whereas the data concerning sperm concentration are conflicting. The age-related changes of semen parameters reflect the histological modifications which are found to varying degrees in individual testes. Men aged >40 years contribute to reduced fertility and fecundity of a couple, especially when the female partner is also of advanced age. Because relatively few children are born to older fathers and genetic diseases are rare, there is little statistical power supporting an association of genetic diseases in the offspring with advancing paternal age. Nevertheless, autosomal dominant diseases and some diseases of complex aetiology, such as schizophrenia, are associated with advancing paternal age. The single point mutations in sperm which are responsible for achondroplasia and Apert's syndrome, two autosomal dominant diseases, increase with the man's age. In case of Apert's syndrome this increase is believed to be due to a pre-meiotic selection of mutant spermatogonia. Although structural chromosome anomalies and disomies of certain chromosomes increase in sperm with the man's age, paternal age is, with the exception of trisomy 21, not associated with numerical or de novo structural chromosomal aberrations in newborns. However, even if the genetic risk for progeny from older fathers is slightly increased, the risk to the individual is low.

Adult↗
PubMed2000

Genomic structure and chromosome location of the gene encoding mouse CD59.

The gene encoding the mouse analogue of the human complement regulator CD59 was cloned using a combination of long range PCR and genomic library screening. Sequence obtained showed that its genomic structure closely resembled that of the human CD59 gene, comprising 4 exons, each separated by a long intron region. The sizes of introns and exons were comparable to those of the human gene with the exception of the third intron which is 2.5 kb in the mouse compared to 7 kb in the human gene. All exon/intron boundaries conformed to the GT-AG rules for splicing. Radiation hybrid mapping localised mouse Cd59 between D2Mit333 and D2Mit127 on chromosome 2, a region homologous with human chromosome 11p13 where the human CD59 gene is localised. These data have permitted the construction of a gene targeting vector for the generation of transgenic mice deficient in CD59.

Animals↗
PubMed2002

C. elegans condensin promotes mitotic chromosome architecture, centromere organization, and sister chromatid segregation during mitosis and meiosis.

Chromosome segregation and X-chromosome gene regulation in Caenorhabditis elegans share the component MIX-1, a mitotic protein that also represses X-linked genes during dosage compensation. MIX-1 achieves its dual roles through interactions with different protein partners. To repress gene expression, MIX-1 acts in an X-chromosome complex that resembles the mitotic condensin complex yet lacks chromosome segregation function. Here we show that MIX-1 interacts with a mitotic condensin subunit, SMC-4, to achieve chromosome segregation. The SMC-4/MIX-1 complex positively supercoils DNA in vitro and is required for mitotic chromosome structure and segregation in vivo. Thus, C. elegans has two condensin complexes, one conserved for mitosis and another specialized for gene regulation. SMC-4 and MIX-1 colocalize with centromere proteins on condensed mitotic chromosomes and are required for the restricted orientation of centromeres toward spindle poles. This cell cycle-dependent localization requires AIR-2/AuroraB kinase. Depletion of SMC-4/MIX-1 causes aberrant mitotic chromosome structure and segregation, but not dramatic decondensation at metaphase. Moreover, SMC-4/MIX-1 depletion disrupts sister chromatid segregation during meiosis II but not homologous chromosome segregation during meiosis I, although both processes require chromosome condensation. These results imply that condensin is not simply required for compaction, but plays a more complex role in chromosome architecture that is essential for mitotic and meiotic sister chromatid segregation.

Adenosine Triphosphatases↗
PubMed1999

Genomic structure and chromosome location of RPL27A/Rpl27a, the genes encoding human and mouse ribosomal protein L27A.

The intron-containing genes encoding human and mouse ribosomal protein (r-protein) L27A were cloned and sequenced. The human r-protein L27A gene (RPL27A) shared an identical exon/intron structure with the mouse r-protein 27A gene (Rpl27a). The translational start codon ATG was separated from the main reading frame by the first intron sequence in both genes. An approximately 200-bp sequence upstream of the translational start site of both genes displayed remarkable similarity, and contained the putative promoters lacking canonical TATA, but harbored Sp1 binding sites and a short stretch of pyrimidine cluster, similar to other r-protein genes. Transcriptional regulatory elements, Box-A and GABP, found in the promoters of some other r-protein genes were also conserved in both genes. These structural features were included in the typical CpG island identified in the 5'-end sequences, suggesting that RPL27A/Rpl27a cloned here are authentic and transcriptionally active. Fluorescence in situ hybridization (FISH) analysis localized the mouse intron-containing Rpl27a to chromosome 7E2-F1 syntenic to human chromosome 11p15, where human RPL27A was located.

Animals↗
PubMed1998

Complete cDNA sequence, genomic structure, and chromosomal localization of the LPA receptor gene, lpA1/vzg-1/Gpcr26.

The lpA1/Gpcr26 locus encodes the first cloned and identified G-protein-coupled receptor that specifically interacts with lysophosphatidic acid. A murine full-length cDNA of size consistent with that seen on Northern blots (3.7 kb) was determined using 3' rapid amplification of cDNA ends. Analysis of genomic clones revealed that the gene is divided into five exons, with one intron inserted in the coding region for transmembrane domain VI and one exon encoding the divergent 5' sequence in another published cDNA clone variant (orphan receptor mrec1.3). This structure differs from the intronless coding region for a homologous receptor, Edg1, but is identical to another more similar orphan receptor (lpA2) that has been deposited with GenBank. Using backcross analysis, both exons 1 and 4 mapped to a proximal region of murine Chromosome 4 indistinguishable from the vacillans gene. Exon 4 also mapped to a second locus on proximal Chromosome 6 in Mus spretus, and this partial duplication was confirmed by Southern blot. The genomic structure indicates a distinct, divergent evolutionary lineage for the vzg-1/lpA1 subfamily of receptors compared to those of homologous orphan receptor genes.

Amino Acid Sequence↗
PubMed1999

Type and frequency of chromosome aberrations in 781 couples undergoing intracytoplasmic sperm injection.

Cytogenetic investigations were performed in 781 couples prior to intracytoplasmic sperm injection (ICSI) because of severe male infertility or fertilization failures in previous in-vitro fertilization attempts. Out of these 1562 patients, 1012 had a normal karyotype without any aberrations (64.8%), 204 patients had an abnormal karyotypes (13.1%). These chromosome aberrations included constitutional aberrations (4.4%), fragile sites of autosomes (3.0%), low level mosaicism of sex chromosomes (4.0%) and secondary structural chromosome aberrations (4.2%). Combinations of different types of abnormalities were stated. Another 346 patients (22.1%) showed single cell aberrations; the significance of these is unclear at the moment. Constitutional chromosome aberrations were detected in 69 patients. The following chromosome aberrations were observed: 35 sex chromosomal aberrations (comprising hyperploidies of X or Y chromosomes, mosaicisms and derivative X and Y chromosomes), 34 autosomal aberrations including 14 reciprocal translocations, five Robertsonian translocations, six inversions, one marker chromosome, one trisomy 18 mosaicism and seven other structural aberrations. Three autosomal regions showed fragile sites: 6q13 in 2.9% of the patients, 17p12 and 10q24 in 0.05% each. In conclusion, our data show that a high number of infertile couples in an ICSI programme are affected by chromosome aberrations which occur in both sexes. It is suggested that a chromosomal analysis should be performed on both partners before ICSI treatment is initiated.

Chromosome Aberrations↗