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PubMed1981

FUdR induction of the X chromosome fragile site: evidence for the mechanism of folic acid and thymidine inhibition.

Experiments designed to illuminate the mechanism by which folic acid and thymidine inhibit expression of the Xq28 fragile site in human lymphocytes are described. The fragile site is induced by 5-fluorodeoxyuridine (FUdR), a potent inhibitor of thymidylate synthetase, in the presence of otherwise inhibiting concentrations of folic acid but not in the presence of thymidine. These results indicate that the fragile site is expressed because of depletion of deoxythymidine monophosphate (dTMP) available for DNA synthesis.

Cells, Cultured↗
PubMed2004

Chromosome fragility in two sheep flocks exposed to dioxins during pasturage.

In the last 3 years several farms raising cattle, river buffalo and sheep have been unable to sell dairy milk due to the presence of high levels of dioxins. Furthermore, several cases of abortion (around 25% of total births) and abnormal foetuses (2.5% of total births) were recorded in two flocks of sheep raised in the province of Naples where a higher level of dioxins (5.27 pg/g fat, as human WHO TCDD equivalent) have been found in the milk mass than that permitted (3.0 pg/g fat, as human WHO TCDD equivalent). Cytogenetic investigations were carried out on 24 sheep (all females), randomly sampled from the two different flocks, one abnormal foetus and 11 female sheep (control) raised approximately 80 km from the area where the two exposed flocks were raised. Frequencies of aneuploid cells, gaps, chromatid breaks, chromosome breaks, fragments and sister chromatid exchange (SCE) were determined. While no differences were observed between the number of aneuploid cells (15% of total cell population) of both exposed animals and controls, significant (P < 0.001) increases in the frequencies of other chromosome abnormalities (mean chromosome abnormality/cell = 0.76 +/- 1.1) and SCEs (mean SCE/cell = 9.4 +/- 3.7) were found in the exposed animals, compared with the control (mean chromosome abnormality/cell = 0.18 +/- 0.4; mean SCE/cell = 7.1 +/- 3.0). Significantly higher values of SCEs (mean SCE/cell = 10.9 +/- 4.4) were also found in the abnormal foetus compared with the control. Chemical analyses on soil, grass and water at two sites where the two flocks were pastured established that doses of dioxins (17 different types) were below the legally permitted limits.

Aneuploidy↗
PubMed1984

Detection of the fragile X chromosome and other fragile sites.

To assist in cell sample size selection and detect the fragile X chromosome, statistical tables have been presented. A comparable approach had been suggested earlier for the diagnosis of chromosome mosaicism. The cytologic detection of the fragile X or any fragile site is simply a special case in the detection of mosaicism. Minimum numbers of metaphases are recommended for fragile X analysis to have 95% confidence that the fragile X is not manifest in a given proportion of cells and similar recommendations apply to all other fragile sites.

Cell Count↗
PubMed1995

The molecular basis of fragile sites in human chromosomes.

Fragile sites on chromosomes have been classified into a number of groups according to their frequency and the conditions required to induce them. A number of the rare folate-sensitive fragile sites have been characterized and shown to be amplified methylated CCG trinucleotide repeats. One common fragile site has been partly characterized and appears to be a region of fragility, rather than a single site.

Aphidicolin↗
PubMed1994

Localization of the fragile X chromosome break points in Holstein-Friesian cattle (Bos taurus).

Chromosome fragility is generally believed to affect cattle reproductive performance. Lymphocytes were cultured and the long arm of the X-chromosome was measured in 19 bovines that had been presented as repeat breeders, freemartin cotwins, or as having had anestrus or abortions. The positions of the break points on the X-chromosome were estimated by a measuring compass, starting at the centromere. Relative measurements were calculated from the ratio of break point distance from the centromere to the total Xq length. In our study the break points were found to be mainly in the middle of the long arm (X = 0.52; sigma=0.046). Giemsa banding showed that the break points were located in a large negative G-band observed in region 3 of the long arm. The relationship of these findings to animal reproductive problems is discussed.

Journal Article↗
PubMed2001

Fragile and unstable chromosomes in cancer: causes and consequences.

Cancer cells commonly exhibit various forms of genetic instability, such as changes in chromosome copy number, translocations and point mutations in particular genes. Although transmissible change seems to be an essential part of the neoplastic process, the extent to which DNA instability is a cause rather than a consequence of cancer is unclear. Chromosomal fragile sites have been proposed to be not only susceptible to DNA instability in cancer cells, but also associated with genes that contribute to the neoplastic process. Mutation at fragile site loci might therefore have a causative role in cancer. Recent studies on one class of human chromosomal fragile sites show that instability at fragile site loci can functionally contribute to tumor cell biology.

Animals↗
PubMed2000

The clinical significance of fragile sites on human chromosomes.

Fragile X syndrome is now a well established common clinical entity and most of those who are aware of the condition probably know that it takes its name from a rare fragile site (FRAXA) on the X chromosome. This is the best known fragile site and its clinical significance is clear. Similar, but a little less known is FRAXE, a fragile site close to that associated with fragile X syndrome, but in this case associated with a mild form of non-specific X-linked mental retardation. These are the only two fragile sites that are unequivocally of clinical significance. A fragile site within the CBL2 oncogene on chromosome 11 has been mapped very close to the deletion breakpoint in a handful of patients with Jacobsen syndrome. It is doubtful that parents with FRA11B are at increased risk of having children with Jacobsen syndrome, but this cannot be ruled out. The common fragile sites have been implicated in oncogenesis since shortly after their discovery in the early 1980s. While a couple of these are within genes that have been implicated in cancer it is unclear whether either the fragile sites, or the genes in which they are located are important in cancer. It may be that the common fragile sites are regions of genomic instability and that this instability is increased in malignant cells, analogous to the enhanced instability seen at microsatellite loci in a number of tumours. Since we all have the common fragile sites there is no suggestion that they give anyone an increased risk of developing malignant disease. In dealing with patients who are found to have fragile sites, other than FRAXA, FRAXE and possibly FRA11B, considerable reassurance can be given that they are not at increased risk of having children with congenital disease or developing disease themselves because of their fragile sites.

Chromosome Aberrations↗
PubMed1988

[Mental deficiency associated with a fragility of the X chromosome].

Fragile X chromosome was studied in 44 male and 9 female children, affected of mental retardation. In 10 males fragile X was positive. All this patients presented mild mental deficiency with and IQ from 55 to 75. Behaviour was generally hyperkinetic except one autistic boy. Most frequent dysmorphic signs were increased head circumference and prominent large ears. Family history for mental retardation was positive almost in all cases. High percentage of children with fragile X syndrome (22.7%) encountered among male patients suggest convenience of screening, for these anomaly, of all boys affected of mild mental deficiency and all those with an autistic behaviour although lacking of dysmorphic characteristics. This will allow to know more on etiology and to offer genetic counseling to families. Although study in girls was negative, authors believe it is interesting to screen fragile X because some females with border line retardation present this chromosomic anomaly.

Adolescent↗
PubMed1987

A heritable fragile 12q24.13 segregating in a family with the fragile X chromosome.

A fragile site on chromosome 12, at 12q24.13, was found in the lymphocytes of two members of a family during the study for detection of a fragile X chromosome. The site was found to be heritable and folate-sensitive, and it fulfills all four criteria for a fragile site. It thus can now be confirmed as the heritable fragile site FRA12C.

Adolescent↗
PubMed1993

Folate sensitive common fragile sites in chromosomes of the domestic pig (Sus scrofa).

Chromosomal fragile sites were studied in blood lymphocytes of the pig after induction with 0, 5, 10 and 20 micrograms of fluorodeoxyuridine (FudR) ml-1 of culture. The percentage of cells showing fragile sites and total breaks and gaps in 100 cells was significantly higher in all treated cultures than the control (P < 0.001). A concentration of 5 to 10 micrograms of FudR ml-1 of medium is recommended as the optimum for mitotic index and fragile site expression in the pig. Localisation of the fragile sites was by GTG banding after destaining of the conventionally stained Giemsa preparations. Common fragile sites in the pig were identified in 24 sites on 10 chromosomes. Some fragile sites corresponded to the breakpoints in known reciprocal translocations.

Animals↗
PubMed1987

Cytogenetic instability in a family with gastric cancer recurrence.

An index case with a congenital malformation syndrome enabled detection of a family that had a previous history of spontaneous abortuses and recurrence of neoplasia through three generations. Cytogenetic analysis performed on lymphocytes from 11 subjects in the second and third generation showed karyotypic alterations in both tumor bearers and apparently normal subjects. Chromosome variations consisted of: spontaneous chromosome fragility; chromosome translocations; polymorphisms in the heterochromatic regions in chromosomes Y, #1, #16, #22. The inheritance pattern of all chromosome rearrangements and heteromorphisms observed was established starting with the second generation, and the contribution of specific individuals was identified. Although the relationship between chromosomal instability and predisposition to gastric cancer does not appear to be coincidental, no specific chromosome alteration in normal somatic cells was shared by all members of the family who developed or are at risk of developing tumors.

Adult↗
PubMed1992

Clustering of C2-H2 zinc finger motif sequences within telomeric and fragile site regions of human chromosomes.

Ninety-three phage clones identified by hybridization with a C2-H2 zinc finger sequence probe have been grouped into 23 genetic loci. Partial sequencing verified that each locus belonged to the zinc finger family. Oligonucleotide primer pairs were developed from these sequences to serve as STS markers for these loci. One or more clones from each locus was mapped onto human metaphase chromosomes by fluorescence in situ hybridization. Several loci map to identical chromosomal regions, indicating the possible presence of multigene clusters. Zinc finger loci were found to reside predominantly either in telomeric regions or in chromosomal bands known to exhibit chromosome fragility. Chromosome 19 carries a disproportionate fraction (10 of 23) of the mapped zinc finger loci.

Amino Acid Sequence↗