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Results for “Chromosome Fragility”

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PubMed1990

Genetic determination of fragile-site expression.

To explore genetic effects on the expression of chromosomal fragile sites in vitro, we studied the expression of common fragile sites (c-fra) in cultured lymphocytes of a human chimera (Chi46,XX/46,XY). Since the two cell lines in the chimera share the same environment in vitro and in vivo on cell culture preceding chromosome analysis, differences in the expression of c-fra must be due to genetic factors. The peripheral lymphocytes were cultured in medium 199 and in medium RPMI 1640 with and without aphidicolin. All lesions were localized after GTG-banding and mapped to the human idiogram. In the cultures with aphidicolin the XX cells showed, at high (0.4 microM) APC levels, a significantly higher expression of c-fra than did the XY cells. This difference between cell lineages was not confined to certain individual c-fra; rather it was seen for practically all of them. Therefore, we conclude that there are genetic factors which influence the propensity of c-fra to be expressed. Whether sex is one of these factors, or perhaps even the most important one, still has to be elucidated.

Aphidicolin↗
PubMed2003

Fragile sites and bladder cancer.

Continued reports of associations between environmentally induced chromosomal fragile sites and cancer prompted us to undertake a review of current literature to examine whether there might be a relationship between fragile sites and chromosomal alterations reported for bladder cancer. It was found that more than half (56%; odds ratio [OR] = 4.70) of chromosomal rearrangements reported for bladder cancer were located at 77 (65%) of the 118 recognized fragile sites (OR = 6.88). Furthermore, 55% of the fragile sites implicated coincided with one or more genes that have been associated with human cancer (such as oncogenes, tumor suppressor, relonc, transloc, disorder, apoptotic, and angiogenic genes). The most common fragile sites involved were FRA1D, FRA1F, FRA8C, FRA9D, FRA9E, and FRA11C. This correlation suggests that there may be profiles of genetic damage via fragile site expression that lead to the development of at least a proportion of bladder cancers.

Aphidicolin↗
PubMed1999

Bleomycin-induced chromosome aberrations in lymphocytes derived from patients with lamellar ichthyosis.

Patients affected by some genetic skin defects, for example, dyskeratosis congenita or scleroderma, may present spontaneous or induced chromosomal fragility. Hence we performed a cytogenetic analysis in families of patients affected by lamellar ichthyosis, an autosomal recessive disease not yet fully characterized at the cellular and molecular levels. Chromosomal fragility was assayed in untreated lymphocyte cultures and in those supplemented with aphidicolin or bleomycin. Cells from some affected patients and some of their parents showed hypersensitivity to the radiomimetic agent bleomycin.

Bleomycin↗
PubMed1992

Aphidicolin-inducible common fragile-site expression: results from a population survey of twins.

Common chromosomal fragile sites appear to be ubiquitous in humans and other mammals, and, although the molecular basis and function of these sites remain an enigma, it has been speculated that they may be a cytogenetic expression of gene activity. A population survey of 28 twin pairs was conducted to assess the heritability of common fragile-site expression. Our data yielded a heritability estimate of .88 for total site expression, suggesting that these sites may result from some common process that is under relatively stringent genetic control. An analysis of the expression of individual autosomal sites revealed that expression on both homologues in the same cell occurred more frequently than expected.

Adolescent↗
PubMed2000

Replication delay along FRA7H, a common fragile site on human chromosome 7, leads to chromosomal instability.

Common fragile sites are specific chromosomal loci that show gaps, breaks, or rearrangements in metaphase chromosomes under conditions that interfere with DNA replication. The mechanism underlying the chromosomal instability at fragile sites was hypothesized to associate with late replication time. Here, we aimed to investigate the replication pattern of the common fragile site FRA7H, encompassing 160 kb on the long arm of human chromosome 7. Using in situ hybridization on interphase nuclei, we revealed that the replication of this region is initiated relatively early, before 30% of S phase is completed. However, a high fraction ( approximately 35%) of S-phase nuclei showed allelic asynchrony, indicating that the replication of FRA7H is accomplished at different times in S phase. This allelic asynchrony is not the result of a specific replication time of each FRA7H allele. Analysis of the replication pattern of adjacent clones along FRA7H by using cell population and two-color fluorescent in situ hybridization analyses showed significant differences in the replication of adjacent clones, under normal growth condition and upon aphidicolin treatment. This pattern significantly differed from that of two nonfragile regions which showed a coordinated replication under both conditions. These results indicate that aphidicolin is enhancing an already existing difference in the replication time along the FRA7H region. Based on our replication analysis of FRA7H and on previous analysis of the common fragile site FRA3B, we suggest that delayed replication is underlying the fragility at aphidicolin-induced common fragile sites.

Cell Line↗
PubMed1984

Cytogenetic study in 50 couples with recurrent abortions.

The presence of chromosome abnormalities in couples with repeated spontaneous abortion is known even if the phenomenon is far from a complete assessment. A cytogenetic investigation in 50 couples with a history of two or more spontaneous abortions is referred to in this study. A peripheral blood lymphocyte culture was harvested for each subject and the slides were stained by G- and C-banding. Of the 100 individuals examined, 4 were carriers of balanced translocations, 3 of which were of the Robertsonian type. A chromosomal fragility (chromatidic and/or chromosomic gaps) was seen in 2 cases. The incidence of balanced translocations found here is 8% which is near to the mode (about 9%) observed in previous studies. Those frequencies are greater than in the general population (0.1-0.4%). This indicates that balanced translocations have some importance in causing abortion while this is not the case for other chromosomal abnormalities (e.g. pericentric inversions). Thus, cytogenetic analyses should be recommended in couples with repeated spontaneous abortions, when clinical data fail to clarify the cause.

Abortion, Habitual↗
PubMedDate not supplied

Cerebroretinal vasculopathy and leukoencephalopathy mimicking a brain tumor. Report of two early-onset cases with Fanconi's anemia-like phenotypes suggesting an autosomal-recessive inheritance pattern.

We report two sisters affected with a unique disorder characterized by recurrent space-occupying brain lesions and retinal vasculopathy since their early twenties. Affection status was associated with abnormalities characteristic of Fanconi's anemia, i.e. aplastic anemia, microcephaly, short stature, an unusual face and pigmentation abnormalities of skin. In cytogenetic analyses performed in childhood signs of chromosome fragility or any chromosomal aberration were lacking. Histopathological examination of brain biopsy samples in both cases demonstrated identical histomorphological features of an unusual occlusive vasculopathy with multilayered basement membranes and coagulation necroses which were confined to the white matter. A veno-occlusive retinopathy with neovascularization attributed to progressive visual loss. One of the sisters died at an age of just 24 years, the other is now 27 years old. Unlike any other published cases of hereditary cerebroretinal vasculopathy, the sisters' complex early-onset vaso-occlusive CNS-/eye-disease seems to be genetically associated with their Fanconi's anemia-like phenotypes and is suggested to constitute an autosomal-recessive variant. Patchy white matter calcifications, an incidental finding in either of the affected sisters, may represent preclinical manifestation of disease onset in childhood.

Adult↗
PubMed1988

The use of early simultaneous percutaneous umbilical blood sampling (PUBS) and amniocentesis for prenatal fragile X chromosome diagnosis.

Early simultaneous percutaneous umbilical blood sampling (PUBS) and amniocentesis for prenatal diagnosis were undertaken for the first time in a 17-week gestation fetus at risk for the fragile X [fra (X)] syndrome. Metaphase spreads from 300 fetal lymphocytes were examined within 5 days following PUBS, while approximately 5 weeks were required for the analysis of 148 amniocytes. The chromosomes were interpreted as normal (46,XX) and the fetus as fragile X-negative at the time of prenatal diagnosis. This was cytogenetically confirmed after delivery of a healthy term female infant. Our results suggest that early PUBS may become a useful adjunct to amniocentesis because of shorter culture time and earlier diagnosis.

Amniocentesis↗
PubMed2004

Cancer prevention and therapy in a preclinical mouse model: impact of FHIT viruses.

A link between common chromosome fragile sites and frequent chromosomal deletions in cancer was observed two decades ago and led to the hypothesis that genes at fragile sites may play a role in tumor development. In 1996, the human fragile histidine triad gene, FHIT, was identified by positional cloning of the chromosome region spanning the carcinogen-sensitive, common fragile site, FRA3B at 3p14.2. Loss or inactivation of the FHIT gene in a large fraction of human tumors results in absence or reduction of Fhit protein. In vitro analyses and in vivo tumorigenicity studies show that restoration of Fhit protein induces tumor suppression in 50% of tumor cell lines tested. Viral vector-mediated FHIT gene transfer to Fhit-deficient mice not only prevents but reverses the carcinogen-induced tumor development in vivo, in accordance with the oncosuppressive properties of Fhit protein. The strong proapoptotic activity following Fhit infection of cancer cells strengthens the case for further exploration of FHIT gene therapy in cancer prevention and treatment.

Acid Anhydride Hydrolases↗
PubMed1992

Increased genetic instability of the common fragile site at 3p14 after integration of exogenous DNA.

We determined previously that the selectable marker pSV2neo is preferentially inserted into chromosomal fragile sites in human x hamster hybrid cells in the presence of an agent (aphidicolin) that induces fragile-site expression. In contrast, cells transfected without fragile-site induction showed an essentially random integration pattern. To determine whether the integration of marker DNA at fragile sites affects the frequency of fragile-site expression, the parental hybrid and three transfectants (two with pSV2neo integrated at the fragile site at 3p14.2 [FRA3B] and specific hamster fragile sites [chromosome 1, bands q26-31, or mar2, bands q11-13] and one with pSV2neo integrated at sites that are not fragile sites) were treated with aphidicolin. After 24 h the two cell lines with plasmid integration at FRA3B showed structural rearrangements at that site; these rearrangements accounted for 43%-67% of the total deletions and translocations observed. Structural rearrangements were not observed in the parental cell line. After 5 d aphidicolin treatment, the observed excess in frequency of structural rearrangements at FRA3B in the cell lines with pSV2neo integration at 3p14 over that in the two lines without FRA3B integration was less dramatic, but nonetheless significant. Fluorescent in situ hybridization (FISH) analysis of these cells, using a biotin-labeled pSV2neo probe, showed results consistent with the gross rearrangements detected cytogenetically in the lines with FRA3B integration; however, the pSV2neo sequences were frequently deleted concomitantly with translocations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Observations of fragile sites in patients with lymphoma and leukemia.

Chromosomal fragile sites analyses were performed in peripheral lymphocytes of 37 patients with lymphoma and 16 patients with leukemia, and also of 50 healthy individuals as controls. The results were: 1) The rates of chromosomal aberration and frequency of expression of fragile sites in patients with lymphoma and leukemia were significantly higher than those of normal controls. 2) There was a statistical association between 21 of 44 fragile sites and specific cancer breakpoints in patients with lymphoma and this was also the case with 19 of 30 fragile sites and specific cancer breakpoints in patients with leukemia. 3) Concordance between fragile sites and location of oncogenes in the diseases was established. The possible important role of fragile sites in the pathogenesis of lymphoma and leukemia is discussed.

Adolescent↗
PubMed2000

[Fanconi anemia].

Fanconi anemia is a rare autosomal recessive disorder which is characterized with chromosomal fragility and hypersensitivity to DNA cross-link agents. There are large variability in phenotype even among patients of single family. Therefore, diagnosis depends solely on hypersensitivity to DNA cross-link agents. At present at least 8 complement groups are known and 3 genes, FANCA, FANCC and FANCG, have been cloned. There is controversies concerning intracellular localization and interaction between these genes. Although the mechanism of the final effect of products of these genes leading to Fanconi anemia phenotype, chromosomal fragility and ultimately development of cancers is not fully understand, increasing evidence shows that gene products seems to work to prevent oxygen injury by reactive oxygen species rather than repair of DNA injury.

Chromosome Fragility↗
PubMed1982

Fragile X chromosome and X-linked mental retardation.

A family is described in which three normal females transmitted to seven males X-linked mental retardation associated with macro-orchidism and a fragile site on the long arm of the X chromosome -- fra(X)(q27). The affected males also had minor clinical features in common: a large forehead, long face, large ears, a long upper lip and large extremities.

Adolescent↗
PubMed2005

Mapping autosomal dominant progressive limb-girdle myopathy with bone fragility to chromosome 9p21-p22: a novel locus for a musculoskeletal syndrome.

Progressive myopathy of a limb-girdle distribution and bone fragility is a rare autosomal dominant disorder of unknown etiology. Affected individuals, within this family, present with various combinations of progressive muscle weakness, easy fracturing, and poor healing of long bones. Additional features include premature graying with thin hair, thin skin, hernias, and clotting disorders. Electromyograms show myopathic changes and biopsies reveal non-specific myopathic changes. Skeletal radiographs demonstrate coarse trabeculation, patchy sclerosis, cortical thickening, and narrowing of medullary cavities. We report genetic mapping of this disorder to chromosome 9p21-p22 in a multigenerational family. A genome-wide scan for the disease locus obtained a maximal LOD score of 3.74 for marker GATA87E02 N (D9S1121). Haplotype analysis localized the disease gene within a 15 Mb interval flanked by markers AGAT142P and GATA5E06P. This region also localizes diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH). Identification of the disease gene will be necessary to understand the pathogenesis of this complex disorder.

Adolescent↗
PubMed1984

Progressive preleukemia with a chromosomally abnormal clone in a kindred with the Estren-Dameshek variant of Fanconi's anemia.

One of two sisters with hypoplastic anemia and increased chromosomal fragility, but no clinical stigmata of Fanconi's anemia (FA), progressed to preleukemia (with a clone of chromosomally abnormal cells in the bone marrow), and then to acute nonlymphocytic leukemia. The findings indicate that constitutional genetic instability can lead to karyotypically aberrant neoplastic clones in the Estren-Dameshek variant of FA as well as in the more typical chromosomal fragility syndromes.

Adolescent↗