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At least 19 recordsLinked to original sources
PubMed1992

Chromosome fragility and psychopathology in obligate female carriers of the fragile X chromosome.

The relationship between fragility (the percentage of cells exhibiting the fragile X chromosome abnormality) and psychopathological conditions was investigated in a sample of 40 obligate female carriers of the fragile X chromosome. Subjects were categorized by those with positive fragility greater than 0% (n = 19) and those with 0% fragility (n = 21). Compared with women with 0% fragility, it was expected that women with positive fragility would have a higher likelihood of manifesting a spectrum of social and psychological disability previously shown to be associated with fragile X syndrome in women. It was also expected that within the group with positive fragility, degree of fragility would be related to severity of symptoms. Results partially supported the hypotheses: women with fragility over 0% were more likely to be assigned a diagnosis of schizotypal features, were rated higher on symptoms associated with the schizophrenia spectrum, and scored lower on IQ, level of healthiest functioning, education, and socioeconomic status than women with 0% fragility. Subsequent comparisons with a control group indicated that the group with 0% fragility and normal controls did not differ on these variables. Within the group with positive fragility, increasing fragility was related to greater severity of symptoms and lower IQ, education, socioeconomic status, and levels of adaptive functioning, as predicted. Contrary to expectations, positive fragility was not associated with proportion of affective disorder diagnoses or ratings on affective disorder symptoms. The results of the study provide evidence that degree of fragility is a potentially important predictor of psychopathology among women with normal IQ who are carriers of the fragile X chromosome abnormality.

Adult↗
PubMed2002

The fragile histidine triad/common chromosome fragile site 3B locus and repair-deficient cancers.

In various studies of sporadic breast cancers, 40-70% were strongly positive for fragile histidine triad (Fhit) protein expression, whereas only 18% of BRCA2 mutant breast cancers demonstrated strong Fhit expression, suggesting that the BRCA2 repair function may be necessary to retain intact fragile common chromosome fragile site 3B(FRA3B)/FHITloci. In the current study, 22 breast tumors with deleterious BRCA1 mutations were analyzed for Fhit expression by immunohistochemistry in a case-control matched pair analysis. Loss of Fhit expression was significantly more frequent in the BRCA1 cancers compared with sporadic breast tumors (9% Fhit positive versus 68% Fhit positive), suggesting that the BRCA1 pathway is also important in protecting the FRA3B/FHIT locus from damage. To investigate the relationship between repair gene deficiencies and induction of chromosome fragile sites in vitro, we have analyzed the frequency of aphidicolin induction of chromosome gaps and breaks in PMS2-, BRCA1-, MSH2-, MLH1-, FHIT-, and TP53-deficient cell lines. Each of the repair-deficient cell lines showed elevated expression of chromosome gaps and breaks, consistent with the proposal that proteins involved in mismatch and double-strand break repair are important in maintaining the integrity of common fragile regions. Correspondingly, genes at common fragile sites may sustain elevated levels of DNA damage in cells with deficient DNA repair proteins such as those mutated in several familial cancer syndromes.

Acid Anhydride Hydrolases↗
PubMed1985

Linkage studies of X-linked mental retardation: high frequency of recombination in the telomeric region of the human X chromosome (fragile site/linkage/recombination/X chromosome).

One of the commonest forms of X-linked mental retardation is associated with a fragile site at Xq27 on the human X chromosome which can be visualised structurally after culturing cells in folate-deficient media. Unusually, the mutation can be transmitted through a phenotypically normal male. There is already some evidence that the gene loci for G6PD and factor IX are linked to this mental retardation locus. We have followed the inheritance of a DNA sequence 52A, in fragile site families that are also informative for factor IX. We demonstrate that these probes are localised at Xq27/Xq28-Xqter, close physically to the fragile site. We did not find close linkage between 52A, factor IX, and the fragile site in the families studied despite 52A and factor IX showing linkage in normal families. We discuss the importance of these data for the genetic mapping of this region of the human X chromosome and the implication for the use of these DNA probes for clinical diagnosis.

Animals↗
PubMedDate not supplied

Isolated congenital anonychia cases with coincident chromosomal fragility.

Isolated anonychia without any associated phenotypical disturbances is one of the rarest anomalies of congenital nail disorders. Some or all fingers of the hands or feet could be affected. Anonychia can be encountered in dermatologic disorders like pemphigus, lichen planus, epidermolysis bullosa; it can also be seen as a component of some syndromes like Nail-Patella and Cooks syndromes. We present a sister couple in whom all fingernails and toenails were lacking without any additional physical sign. A fragile chromosomal site was also encountered in peripheral chromosome analysis in the long arm of the chromosome 10 in both of the cases.

Abnormalities, Multiple↗
PubMed1986

[Mental retardation and X chromosome fragility].

In four families with mental retardation as cardinal sign, authors found 11 cases of fragile chromosome X, 8 males (most with severe mental deficiency), and 3 females (mothers of affected children). Association of behavior perturbation as uneasiness, and hyperkinesia; facial dysmorphism as long or triangular face, big ears and macroorchidism, postpubertal in most of the cases, allow for clinical diagnosis. Autistic behavior is a suspicion sign too. Authors point out the necessity of a precocious diagnosis in order to treat patients with folic acid and to extend genetic counseling to the families. Prenatal identification is possible and inheritance mode in uncertain, debating recessive form linked to chromosome X and autosomic dominant controlled by sex. Incidence of 1.8/1,000 in newborn males, convert this specific form as the most frequent cause of mental retardation in this sex.

Chromosome Fragility↗
PubMed1987

Protective effect of S-adenosylmethionine against the induction of chromosome fragile sites.

Chromosome fragile sites were induced in the peripheral lymphocytes of 7 donors by treatment of the cells in culture with 5-fluorodeoxyuridine and caffeine. The appearance of these fragile sites was inhibited to a large extent and in a dose-dependent manner by S-adenosylmethionine. It is possible that this methyl donor exerted its protective action through restoration of the correct level of methylation of the DNA.

Caffeine↗
PubMed1998

Instability at chromosomal fragile sites.

Chromosomal fragile sites are loci that are especially prone to forming gaps or breaks on metaphase chromosomes when cells are cultured under conditions that inhibit DNA replication or repair. The relationship of "rare" folate sensitive fragile sites with (CCG)n expansion and, in some cases, genetic disease is well established. Although they comprise the vast majority of fragile sites, much less is known at the molecular level about the "common" fragile sites. These fragile sites may be seen on all chromosomes as a constant feature. In addition to forming fragile sites on metaphase chromosomes, they have been shown to display a number of characteristics of unstable and highly recombinogenic DNA in vitro, including chromosome rearrangements, sister chromatid exchanges and, more recently, intrachromosomal gene amplification. Only one such fragile site, FRA3B at 3p14.2, has been extensively investigated at the molecular level. It extends over a broad region of possibly 500 kb, and no trinucleotide or other simple repeat motifs have been identified in the region. FRA3B has recently been shown to lie within the FHIT gene locus. This region and the FHIT gene are unstable in a number of tumors and tumor cell lines. It thus appears that common fragile sites are also associated with unstable regions of DNA in vivo, at least in some tumor cells, and may cause this instability. Current challenges include determining the mechanism of fragile site expression and instability, and both the environmental and genetic factors that influence this process. Candidate factors include those genes involved in DNA repair and cell cycle and common carcinogens such as those in cigarette smoke.

Acid Anhydride Hydrolases↗
PubMedDate not supplied

Liability to chromosome damage in lymphocytes of "cancer family" subjects: a study of spontaneous and induced chromosomal fragility.

Spontaneous chromosomal fragility was detected in seven tumor patients and one healthy member from two families with a high recurrence of cancer. Major chromosome lesions, such as terminal deletions and rearranged chromosomes, were found at levels significantly higher than those reported for control individuals. The prevalence of these aberrations in comparison to minor ones (chromosome gaps and chromatid breaks) in this group of patients seems to indicate that the fragility observed is the end-point of a process of chromosomal instability, which may have already been brought to expression. Study of other parameters of genetic instability in the most unstable karyotypes showed that the chromosome damage observed was neither paralleled by abnormal SCE frequency nor sustained by defective DNA repair mechanisms or expression of inherited or constitutional fragile sites. As all the subjects investigated here had previously been shown to display intraindividual variations in the C-banded region of chromosome 1, it is possible that spontaneous fragility and acquired C-heterochromatin polymorphism may be markers that, combined with chromosomal instability, create genetic predisposition to cancer.

Adult↗
PubMed2005

Components of DNA damage checkpoint pathway regulate UV exposure-dependent alterations of gene expression of FHIT and WWOX at chromosome fragile sites.

Common chromosome fragile sites are highly recombinogenic and susceptible to deletions during the development of environmental carcinogen-induced epithelial tumors. Previous studies showed that not only genetic but also epigenetic alterations in cancerous cells are involved in inactivation of the genes FHIT and WWOX at chromosome fragile sites, reported to be potential tumor suppressor genes. Here we investigated the effect of UV light on the gene expression. After exposure to UV, the mRNA and protein of the two genes in murine embryonic fibroblasts (MEF) were unstable, apparently at the G1-S phase of the cell cycle, which was consistent with nuclear run-on assay. A study of MEFs synchronized via a double thymidine block indicated that, after the exposure, the expression of Fhit and Wwox was reduced in E2f-1-deficient cells and markedly in wild-type cells, whereas the reduction was partially inhibited in Trp53-deficient cells; cells at the S phase seemed to be sensitive to exogenous FHIT, suggesting a role of the checkpoint at the G1-S phase in the stability of gene expression and a possible involvement of FHIT function at the S phase. The transfection experiment showed that the UV-induced decrease in expression was partially inhibited by transfection of kinase-dead Atr (ataxia telangiectasia mutated and Rad3 related), which is a sensor of UV-induced damage. Taken together, the present study showed that UV-induced alterations of the fragile site gene expression are involved at least partially in the checkpoint function, suggesting the role in the process of carcinogenesis after exposure to UV.

Acid Anhydride Hydrolases↗
PubMed1993

Evidence of chromosomal fragile sites in schizophrenic patients.

Chromosomal fragility and other chromosomal abnormalities were frequently observed in subjects with neuropsychiatric disorders, such as fragile X syndrome, autism or schizophrenia, but only for the first one the fragility is accepted to be associated to a specific pathology, so that it is used as a diagnostic marker. In this study the authors analyzed 50 schizophrenic males, searching for the rare fragile sites or other aberrations with the method suitable for fra(X) detection. Chromosomes from schizophrenic patients resulted more fragile than those from normal controls, especially chromosome 9. The authors discuss the implications of a possible association of these data with the aetiopathogenesis of schizophrenic syndrome.

Chromosome Fragile Sites↗
PubMed2000

A study of chromosomal aberrations and chromosomal fragility after recombinant growth hormone treatment.

Increased chromosomal rearrangements and chromosomal fragility have been previously observed in lymphocytes of children treated with human GH, implying that treatment could predispose to malignancy. Twenty-four children with classic GH deficiency, neurosecretory GH dysfunction, and Turner syndrome were treated with recombinant human GH (0.3 mg x kg(-1) x wk(-1)). Metaphase cells were assessed for spontaneous chromosomal and chromatid aberrations at baseline and 6 mo into treatment. There were no significant differences in aberrations between baseline and the 6-mo samples. However, the mean frequency of chromatid-type aberrations on a per cell basis was significantly higher than at baseline, 0.0088 versus 0.0064 aberrations per cell (p < 0.024). Two patients contributed inordinately to this increase. A third sample from these two patients was almost identical to their baseline samples. Cells were also irradiated in vitro (3 Gy) to assess chromosomal fragility. After irradiation, no patient showed a significant difference for any aberration type, although there was a significantly lower frequency of ring chromosomes on a per cell basis in the 6-mo samples (p < 0.001). We find no evidence that GH therapy influences spontaneous chromosomal aberrations or chromosomal fragility.

Adolescent↗
PubMed2002

Relationship between chromosome fragility, aneuploidy and severity of the haematological disease in Fanconi anaemia.

Fanconi anemia (FA) is a chromosome instability syndrome, characterized by progressive pancytopenia and cancer susceptibility. Other cellular features of FA cells are hypersensitivity to DNA cross-linking agents and accelerated telomere shortening. We have quantified overall genome chromosome fragility and euploidy as well as chromosomes 7 and 8 aneuploidy in peripheral blood lymphocytes from a group of FA patients and age-matched controls that were previously measured for telomere length. The haematology of FA samples were also characterized in terms of whole blood cell, neuthrophil and platelet counts, transfusion dependency, requirement of androgens, cortico-steroids or bone marrow transplantation, and the development of bone marrow clonal cytogenetic abnormalities, myelodysplastic syndrome or acute myeloid leukemia. As expected, a high frequency of spontaneous chromosome breaks was observed in FA patients, especially of chromatid-type. No differences in chromosomes 7 and 8 monosomy, polysomy and non-disjunction were detected between FA patients and controls. The same was true for overall genome haploidy or polyploidy. Interestingly, the spontaneous levels of chromosome fragility but not of numerical abnormalities were correlated to the severity of the haematological disease in FA. None of the variables included in the present investigation (chromosome fragility, chromosome numerical abnormalities and haematological status) were correlated to telomere length.

Aneuploidy↗
PubMed2005

FRA16D common chromosomal fragile site oxido-reductase (FOR/WWOX) protects against the effects of ionizing radiation in Drosophila.

Fragile sites are chromosomal structures that have been proposed to have a determining role in cancer-associated DNA instability. The human WWOX gene spans the FRA16D chromosomal fragile site, the common minimal region of homozygous deletion found in adenocarcinomas and three out of five translocation breakpoints in multiple myeloma. Transcripts from the alternatively spliced WWOX gene encode proteins with common N-terminal WW domains and variable homology to the oxidoreductase family of proteins. In this study, the Drosophila orthologue of the WWOX gene was identified and subjected to mutagenesis via homologous recombination. The resultant DmWWOX1 mutants were viable but exhibited an increased sensitivity to ionizing radiation. This radiation sensitivity was rescued by reintroduction and expression of either the wild-type Drosophila or human WWOX genes. Thus, the protective function of DmWWOX in response to irradiation in Drosophila is conserved with human WWOX (hWWOX). This is consistent with a protective role for hWWOX where aberrant expression, as a result of breakage at the associated fragile site, could contribute directly to cancer progression.

Animals↗
PubMed1989

Spontaneous chromosome fragility in band 3q21, 11p11, or 11q13 of cultured bone marrow cells from two patients with hematologic disorders.

Chromatid gaps and breaks clustering to band 3q21, 11p11, or 11q13 were observed prior to chemotherapy in short-term cultured bone marrow cells from two patients with hematologic disorders, one with acute monoblastic leukemia having +8 as the sole karyotypic abnormality and the other with pernicious anemia having no chromosome abnormality. The mitogen-stimulated peripheral blood lymphocytes of both patients, however, yielded a negligible frequency of chromosome aberrations. Because of no notable history of clastogen exposure in these patients, the observed chromosome fragility is most probably spontaneous, which might be correlated with the patients' physiologic condition at examination, i.e., an unusually low level of folic acid or vitamin B12, both being involved in DNA synthesis. Although band 11q13 is known to contain a common fragile site, chromosome fragility in bands 3q21 and 11p11 has not yet been reported in either normal or neoplastic cells. The present findings appear to favor the in vivo expression of chromosome fragility.

Aged↗
PubMed1998

FRA10B structure reveals common elements in repeat expansion and chromosomal fragile site genesis.

A common mechanism for chromosomal fragile site genesis is not yet apparent. Folate-sensitive fragile sites are expanded p(CCG)n repeats that arise from longer normal alleles. Distamycin A or bromodeoxyuridine-inducible fragile site FRA16B is an expanded AT-rich approximately 33 bp repeat; however, the relationship between normal and fragile site alleles is not known. Here, we report that bromodeoxyuridine-inducible, distamycin A-insensitive fragile site FRA10B is composed of expanded approximately 42 bp repeats. Differences in repeat motif length or composition between different FRA10B families indicate multiple independent expansion events. Some FRA10B alleles comprise a mixture of different expanded repeat motifs. FRA10B fragile site and long normal alleles share flanking polymorphisms. Somatic and intergenerational FRA10B repeat instability analogous to that found in expanded trinucleotide repeats supports dynamic mutation as a common mechanism for repeat expansion.

Alleles↗
PubMed1998

Links between chromatin structure, DNA repair and chromosome fragility.

This paper is a brief overview of the studies we have recently conducted to unravel how chromatin structure and DNA repair modulate the fragility of diverse chromosomes and chromosomal regions. We have employed a combination of molecular cytogenetic techniques, including interphase and metaphase multicolour FISH, reverse FISH with CpG-rich probes or repaired DNA fractions, and several combinations of FISH and immunocytogenetics with antibodies against acetylated histones. The targets of our investigation were human constitutive and facultative heterochromatin, chromosomes with high and low gene density and human and hamster fragile sites. The role of DNA repair was investigated by using DNA repair deficient mutants and DNA repair inhibitors. We found that intragenomic heterogeneity in DNA repair and chromatin structure may explain a substantial part of the differential fragility of diverse chromosomes and chromosomal regions.

Animals↗