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PubMed1998

[A comparison of chromosome fragile sites in elderly and young people].

In this comparative study, the authors investigated the chromosome aberrations and expression of fragile sites in the lymphocytes which were collected from 45 elderly people and 29 young people and were cultured with FUDR for 24 hours. The results showed that the aberration rate was 24.75% for elderly people, but 4.22% for young people (P < 0.01): that the expression of fragile sites was 45.94% for elderly peoples, but 23.02% for young people (P < 0.01): and that the relation of aberrations with fragile sites was 79.98% for elderly people, and 92% for young people. These findings suggest that chromosome aberration is in close association with fragile site.

Adolescent↗
PubMed1985

Enhanced expression of chromosome fragile site 10q25 in chronic myelogenous leukemia.

Spontaneous expression of a BrdU-sensitive fragile site at 10q25 was observed in normal lymphocytes and malignant blood and bone marrow cells in chronic myelogenous leukemia (CML). The cells were marked by a Philadelphia chromosome rearrangement due to insertion of 22q11----q13 at 11q13. The fragile site at 10q25 was expressed in larger proportions of malignant than normal cells. Although this fragile site is not at a cancer chromosome breakpoint, malignancy enhanced its expression, consistent with a cascade effect.

Bone Marrow↗
PubMed2002

Chromosomal fragile sites and relationship between genetic predisposition to small cell lung cancer.

Fragile sites are non-staining gaps and breaks on mammalian chromosomes. Several investigators have pointed out that these sites may act as factors that predispose to specific chromosomal rearrangements that are present in some cancer cases. The expression of common fragile sites induced by aphidicolin (Apc) was evaluated on prometaphase chromosomes obtained from the peripheral blood lymphocytes of 15 patients with lung cancer, 20 of their clinically healthy family members, and 20 age-matched normal controls. As a result of cytogenetic evaluation carried out by the High Resolution Banding (HRB) technique, 1q21, 2q33, 3p14, 7q32, 13q13, 16q23, 17q21, and 22q12 are defined as fragile sites in patients and relatives. The rate of total fragile sites and 2q33, 3p14, and 16q23 are statistically significant in both patients and relatives when compared with the control group. Therefore, our results showed that common fragile sites might be unstable factors in the human genome and they can be used as suitable markers for genetic predisposition to lung cancer.

Adolescent↗
PubMed2001

Identifying chromosomal fragile sites from a hierarchical-clustering point of view.

Identification of fragile sites is a way to investigate the genetic abnormalities that are the hallmark of cancer and play an important role in carcinogenesis. Manifestation of nonrandom breakage at a chromosome band is an essential criterion for determination of the fragility of the band. In this article, a new detection procedure is proposed. This new procedure takes the relationship of one site with the others into consideration and can be applied to tests of the randomness of breakpoints under either the proportional probability model (PPM) or the equiprobability model (EPM). The procedure can form a grouping structure that classifies all sites into several clusters. It is applied to identification of fragile sites for a real data set for Chinese patients with colorectal carcinoma for illustration of the proposed method.

Chromosome Banding↗
PubMed1983

The combined effects of FUdR addition and methionine depletion on the X-chromosome fragile site.

The fragile site on the X chromosome [fra(X)] associated with mental retardation is not normally seen in lymphocytes cultured in media containing folic acid or lacking methionine. The requirement for methionine has been taken to mean that amino acid metabolism or one-carbon transfer via S-adenosyl-methionine is most important in fra(X) expression. The inhibitory effect of folic acid can be overcome, as we have shown, by the addition of 5'-fluorodeoxyuridine (FUdR) to the culture medium, suggesting that depletion of dTMP available for DNA synthesis is most important in expression. We tested the combined effects of FUdR addition and methionine depletion on the fra(X). We found expression of the fra(X), indicating that methionine per se is not necessary for expression. Our work supports the suggestion that expression of the fra(X) is due to specific limitation of the dTMP pool available for DNA synthesis.

Cells, Cultured↗
PubMed2005

Chromosomal translocations in yeast induced by low levels of DNA polymerase a model for chromosome fragile sites.

In the yeast Saccharomyces cerevisiae, reduced levels of the replicative alpha DNA polymerase result in greatly elevated frequencies of chromosome translocations and chromosome loss. We selected translocations in a small region of chromosome III and found that they involve homologous recombination events between yeast retrotransposons (Ty elements) on chromosome III and retrotransposons located on other chromosomes. One of the two preferred sites of these translocations on chromosome III involve two Ty elements arrayed head-to-head; disruption of this site substantially reduces the rate of translocations. We demonstrate that this pair of Ty elements constitutes a preferred site for double-strand DNA breaks when DNA replication is compromised, analogous to the fragile sites observed in mammalian chromosomes.

Chromosomal Instability↗
PubMed1981

[X-linked mental retardation and X-chromosome fragile sites (author's transl)].

One of the commonest forms of mental retardation can now be especially diagnosed by differentiated chromosome analysis: X-linked heritable mental retardation with a fragile site on the X-chromosome. The fragile site on the distal long arm of the X-chromosome in region 2, band 7 (Xq27) is not apparent under normal circumstances of culture but must be provoked by folic acid deficiency in the culture medium. The marker X-chromosome is demonstratable in 4-56% of the metaphases in affected males, whereas the recognition of heterozygote gene carriers is still uncertain. In the hemizygotes the defect is characterised clinically by a usually moderately severe intellectual retardation. The character of the carriers is friendly, and well balanced. Speech development is greatly retarded. Testicular volume beyond puberty is increased. Heterozygote females are usually clinically unremarkable. At times a slight mental retardation has been described.

Culture Media↗
PubMed2006

Molecular cloning of Chinese hamster 1q31 chromosomal fragile site DNA that is important to mdr1 gene amplification reveals a novel gene whose expression is associated with spermatocyte and adipocyte differentiation.

DNA amplification plays important roles in the development of drug resistance and tumor progression. One mechanism of DNA amplification involves the breakage-fusion-bridge (BFB) cycle. We previously reported that in Chinese hamster ovary (CHO) cell line, breakage at fragile site 1q31 was associated with mdr1 gene amplification through the BFB mechanism. To elucidate the molecular basis of BFB-mediated DNA amplification, we cloned 1q31 fragile site DNA from a Chinese hamster cell line containing an integrated neomycin-resistance marker. Sequence analyses revealed many characteristics similar to those in other common fragile sites. Moreover, this fragile site contains an evolutionarily conserved novel gene, designated fragile site-associated (FSA) gene. FSA encodes a approximately 16-kb mRNA, from which an unusually large open reading frame (orf) of 5005 amino acids can be deduced. The C-terminal portion of FSA shares a striking sequence similarity to that of Caenorhabditi elegans lipid depleted-3 (lpd-3) gene whose function has been demonstrated to involve in lipid storage. We also demonstrated that expression of FSA is associated with the developmental programs of spermatogenesis and adipogenesis. Our results suggest that the Chinese hamster 1q31 fragile site has many important functions including regulation of mdr1 amplification and differentiation of adipocytes and spermatocytes.

Adipocytes↗
PubMed1992

[Growth hormone therapy in STH deficiency with immunologic deficiency and chromosome fragility].

A 8 year old boy with short stature, low height velocity, mental retardation, cutaneous abnormalities, common variable immunodeficiency and increased chromosomal instability is described. In this patient growth hormone deficiency could be demonstrated by several stimulation tests. Growth hormone treatment increased growth rate from 4 cm/year before therapy to 7.8 cm in the first and 7.1 cm in the second year of treatment. Under therapy no effect on the immunological reactivity could be observed.

Age Determination by Skeleton↗
PubMed1995

Identifying chromosomal fragile sites from individuals: a multinomial statistical model.

The inability to identify fragile sites from data for single individuals remains the major obstacle to determining whether these chromosomal loci are predisposed to cancer-causing and evolutionary rearrangements. We describe a novel statistical model that is amenable to data from single individuals and that establishes site-specific chromosomal breakage as nonrandom with respect to the distribution of total breakage. Our method tests incrementally smaller subsets of the data for homogeneity under a multinomial model that assigns equal probabilities to a maximal set of nonfragile sites and unrestricted probabilities to the remaining fragile sites with significantly higher numbers of breaks. We show how standardized Pearson's chi-square (X2) and likelihood-ratio (G2) statistics can be appropriately used to measure goodness-of-fit for sparse contingency (individual-based) data in this model. A sample application of this approach indicates extensive variation in fragile sites among individuals and marked differences in fragile-site inferences from pooled as opposed to per-individual data.

Animals↗
PubMedDate not supplied

Spontaneous chromosome fragility in chorionic villus cells.

Human fragile sites are only very rarely expressed spontaneously. In this paper we report the presence of non-random spontaneous chromosome lesions (CL) in chorionic villus samples and their coincidence with fragile site (FS) bands. The average number of CL was about 9% both in RPMI-1640 and in Chang media. To determine any possible influence of external factors other than culture media, the results were grouped according to age of gestation. No differences were observed among the different groups. A total of 101 chromosome lesions could be precisely identified by sequential Leishman Staining/Wright G-banding; 76.2% of them coincided with FS-bands. The most affected region was at 1q12-1q21.1 (15.8% of total CL); other FS with a clustering of breakpoints in our study were 1p36, 1q44, 2q37, 3p24, 3q27, 10q22 and 16q23. These results suggest that spontaneous expression of some FS could be a characteristic of embryonic tissues.

Cells, Cultured↗
PubMedDate not supplied

Psychiatric disability associated with the fragile X chromosome.

Fragile X (or Martin-Bell) syndrome, a common, genetic, mental retardation disorder is increasingly being recognized as a major cause of cognitive disability and psychiatric illness in boys. Here, we present a study in which relatives in 4 generations of a large family with the fra(X) chromosome were given comprehensive psychiatric evaluations in order to further describe the psychopathology associated with this condition. Three of 4 males with the fra(X) chromosome were found to have autistic behavior. An adult fra(X) male had a chronic schizoaffective disorder and mental retardation. In female relatives, a relationship was found between the fra(X) carrier status and psychopathology including schizoaffective and major affective disorders.

Adolescent↗
PubMed2005

Common chromosomal fragile site FRA16D mutation in cancer cells.

Neither the molecular basis for common fragile site DNA instability nor the contribution of this form of chromosomal instability to cancer is clearly understood. Fragile site FRA16D (16q23.2) is within regions of frequent loss-of-heterozygosity (LOH) in breast and prostate cancers, is associated with homozygous deletions in various adenocarcinomas and t(14;16) chromosomal translocations in multiple myeloma. The FOR (WWOX) gene spans FRA16D and encodes a partner of p53 that also has a role in apoptosis. Previously untested 53 cancer cell lines were screened for deletions within the FOR/WWOX gene. Deletions were detected in Co115, KM12C and KM12SM. Homozygous deletions in these and two previously identified tumour cell lines were intragenic on both alleles, indicating a distinct mutation mechanism from that causing LOH. Identical FRA16D deletions in two cell lines (one derived from the primary carcinoma and the other from a secondary metastasis) demonstrate that FRA16D DNA instability can be an early, transient event. Sequence analysis across one deletion locates one endpoint within a polymorphic AT-dinucleotide repeat and the other adjacent to an AT-rich mini-satellite repeat implicating AT-rich repeats in FRA16D DNA instability. Another deletion is associated with de novo repetition of the 9 bp AT-rich sequence at one of the deletion endpoints. FRA16D deleted cells retain cytogenetic fragile site expression indicating that the deletions are susceptible sites for breakage rather than regions that confer fragility. Most cell lines with FRA16D homozygous deletions also have FRA3B deletions, therefore common fragile sites represent highly susceptible genome-wide targets for a distinct form of mutation.

Base Sequence↗
PubMed1998

In vitro effects of growth hormone (GH) and insulin-like growth factor I and II (IGF-I and -II) on chromosome fragility and p53 protein expression in human lymphocytes.

BACKGROUND: We have reported previously that growth hormone (GH) therapy increases cell radiosensitivity; in this study we tested whether GH itself or IGFs induce chromosome aberrations and investigated the expression of p53 protein in response to DNA damage. METHODS: Human peripheral blood lymphocytes were incubated with GH [100 and 1000 microg L(-1)], insulin-like growth factor I [IGF-I; 150 and 1000 microg L(-1)] and IGF-II [600 and 1200 microg L(-1)] for 24 h. The radiomimetic agent bleomycin [BLM; 5 microgm L(-1)] was added in the last 3 h. Cytogenetic analysis was performed by assessing the percentages of damaged cells (%DC) and chromosome aberrations (%CA). The expression of p53 was investigated by flow cytometric assay using the monoclonal antibody DO-7, and expressed as percentage positive cells and mean fluorescence intensity. RESULTS: BLM significantly increased both percentage DC and percentage CA and p53 expression (P < 0.01). The %DC was unaffected by the tested peptides. IGF-I [150 microg L(-1)] increased spontaneous percentage CA (P < 0.01). All peptides further increased the BLM-induced chromosome breakage: GH 100 and 1000 microg L(-1) by 30% and 73% respectively, IGF-I 150 and 1000 microg L(-1) by 41% and 96% respectively and IGF-II 600 and 1200 microg L(-1) by 89% and 45% respectively. The spontaneous and BLM-induced expression of p53 was unaffected by GH, whereas it was significantly increased by IGFs (P < 0001). CONCLUSIONS: These results indicate that the DNA-damaging effect of BLM is amplified by GH and, more markedly, IGF-I and -II. IGF-I and -II also stimulate p53 protein expression that, taking part in DNA repair, may counteract the IGF action on genome stability.

Bleomycin↗