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Results for “Chromosome Fragility”

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At least 235 records · Page 13Linked to original sources
PubMed1991

Replication status of the fragile X chromosome and its implications for reproductive performance in the Indian mole rat (Nesokia indica).

In all fertile females the fragile X chromosome was almost always late replicating (inactive) in an average 82% of cells whereas in infertile females, it was early replicating (active) in about the same percentage of cells. These observations strongly suggest a correlation between the replication (activity) status of the fragile X chromosome and reproductive performance.

Animals↗
PubMed1984

[Mental retardation linked to fragility of chromosome X: current knowledge].

The association of the fragile X chromosome with X-linked mental retardation is now well established. The main clinical features are mental retardation, typical facial dysmorphism and macroorchidism. Cytogenetically there is a fragile site in band Xq27-28 which can be demonstrated using specific techniques. The genetic studies are compatible with a X-linked dominant inheritance with an incomplete penetrance. A preliminary estimation of an overall frequency of 1: 2000 males for the fra(X)(q) condition is suggested.

Bromodeoxyuridine↗
PubMedDate not supplied

Analysis of FMR1 and flanking microsatellite markers in normal and fragile X chromosomes in Portugal: evidence for a "protector" haplotype.

In order to look for linkage disequilibrium between the fragile X locus and its flanking markers, we analysed the FRAXAC1 and DXS548 microsatellites in normal and fragile X individuals of Portuguese origin. We observed differences in allele and haplotype frequencies between these two samples. Four haplotypes (A-2, C-2, C-5 and D-6) accounted for 76% of all fragile X chromosomes, whereas a single haplotype (C-7) accounted for 70% of the normal population and less than 3% of the fragile X chromosomes. Among the four observed high-risk haplotypes, A-2 and D-6 had been previously reported in other studies, but C-2 and C-5 seem characteristic of Portuguese patients, as suggested by the high frequency (38%) in fragile X chromosomes and virtual absence in controls. In accordance with previous studies, a greater heterozygosity of the fragile X sample was noted when compared to that of controls. The high frequency of C-7 haplotype in the normal population and its virtual absence in the fragile X sample may reflect the existence of linkage disequilibrium between the two loci and/or selective advantage (protector effect) of this haplotype.

Fragile X Messenger Ribonucleoprotein 1↗
PubMed1984

Expression of fragile X chromosome in human-rodent somatic cell hybrids.

The fragile X chromosome, associated with a common form of X-linked mental retardation, is cytologically observed most often as a gap or fragile site near the distal end of the long arm in band Xq28. Expression of this site is variable and dependent upon lowered thymidylate pools. In order to examine the behavior of this fragile site in a foreign genetic background, interspecific somatic cell hybrids were isolated from crosses of hamster cells and lymphoblastoid cells derived from male patients with fragile X-linked mental retardation. Three hybrid cell lines containing the human X chromosome were analyzed. Following induction with 5-fluorodeoxyuridine, all three hybrids expressed the fragile site in approximately 10% of the metaphases examined. Our data indicate that expression of the fragile site in band Xq27 is dependent neither on the integrity of the human genome nor on the expression of human autosomal genes.

Animals↗
PubMedDate not supplied

Possible erasure of the imprint on a fragile X chromosome when transmitted by a male.

Although most males with the fragile-X [fra(X)] syndrome do not reproduce, there are 2 published pedigrees that include affected males who have daughters and who thus appear to have transmitted the fragile-X chromosome to their progeny. In addition, one published fra(X) pedigree includes an apparently normal male who expresses cytogenetically the fra(X) site at high frequency and who has 3 daughters. In the 6 daughters of these 3 males, there is little or no cytogenetic expression of the fra(X). I interpret these pedigrees within the context of my X-inactivation imprinting model of the fra(X) syndrome (Genetics 117:587-599): the cytogenetic manifestation of the imprinted state of the mutant fra(X) chromosome [high percentage of cytogenetic expression] is no longer present in daughters of imprinted males. I propose that the imprinted state is erased when an imprinted fragile-X chromosome is passed through a male. Such erasure in the gender opposite to the gender that established the imprint is in accord with other examples of chromosome imprinting in mammals. Additional data from unpublished fra(X) pedigrees are requested.

Adult↗
PubMed1993

The identification of a third fragile site, FRAXF, in Xq27--q28 distal to both FRAXA and FRAXE.

FRAXA is unique amongst fragile sites in that it is intimately involved with a specific clinical phenotype, the fragile X syndrome. Whilst the majority of fragile X individuals have been found to have a characteristic mutation in the FMR1 gene, a small proportion of individuals exhibiting fragility have no such mutation. Investigation of the site of chromosome fragility in these FMR1 mutation negative, fragile X site positive individuals, has identified a second site of fragility, FRAXE. However, the presence of FRAXE has not explained all such cases. Here we describe a fragile X site positive, FMR1 mutation negative family, in which chromosome fragility is not due to the FRAXA or FRAXE but is due to a third site designated FRAXF. Using fluorescent in situ hybridisation (FISH) this site is shown to lie over 1Mb distal to FRAXA. The identification of a third fragile site in this small region of the X chromosome provides an opportunity to extend our studies of the molecular nature of chromosome fragility.

Adolescent↗
PubMed1995

[Diseases due to instability of DNA].

The catalog of genetic diseases whose mutational mechanisms are based on the expansion of nucleotide triplets includes 8 disorders classified in terms of type of triplet sequence and the mechanism by which the mutation manifests clinically. To date there are 3 groups. The first is made up of several mental retardation syndromes linked to fragility in the X chromosome (FRAXA, FRAXE, FRAXF, FRA16), with CGG type triplets and large growth expansions located close to a CpG island whose methylation determines degree of chromosome fragility as well as the size of expansion. The second group encompasses diseases arising from CAG triplets. Examples are spinal bulbar atrophy, Huntington's chorea (HC), type 1 dominant cerebellar ataxia (DCA1), dentatorubral-pallidoluysian atrophy (DRPLA) and Machado-Joseph's disease. In this group the expansion codes a polyglutamate residue that gives rise to clinical manifestations by way of functional gain. Myotonic dystrophy (MD) remains in a separate group, with large-size expansion but no chromosomal fragility, and clinical manifestations in multiple systems. All entities encompass phenotypic variation or tendency to inter-generational growth of the expanded fragment that triggers the anticipation phenomenon to varying degrees--greater for some diseases (MD) in cases of maternal transmission and for others (DCA1, HC and DRPLA) when transmission is paternal. The mechanisms by which expansions occur is unknown but the decisive element in some entities may be failure to correct errors in DNA duplication and errors in the integrity of the repeated sequence. We review the difficulties inherent in establishing correlations between genotype and phenotype and in providing genetic counseling.

Chromosome Aberrations↗
PubMed1995

Study of the relationships between common fragile sites, chromosome breakages and sister chromatid exchanges.

This paper reports the results of an investigation into the relationship between common fragile sites and sister chromatid exchanges (SCE). Human leukocyte cultures were grown in two different media, one complete (RPMI 1640) and one deficient in folic acid and thymidine (199M). Some of the cultures were treated with DAPI, a non-intercalating compound which binds preferentially to the AT bases of DNA and is capable of inducing fragile sites. Bromodeoxyuridine (BrdU) was added to all the cultures for SCE analysis. Chromomycin A3 was used for mapping lesions and SCEs by R-banding. A total of 400 cells was examined. The main results show that: BrdU, probably by re-equilibrating the unbalanced nucleotide pool of the 199 culture medium, interferes with the synergism between this culture medium and DAPI in inducing the expression of fragile sites; the SCE frequency per cell is not increased by DAPI in both culture media, therefore this compound does not seem to cause any damage to the DNA and seems merely to act by inhibiting the normal condensation of a subset of fragile sites that possess DAPI-specific base sequences; even in the absence of chromosomal lesions, the fragile sites are significantly preferred as SCE sites to non-fragile sites, whereas in the presence of a lesion, both fragile and non-fragile sites have the same likelihood of undergoing SCE. All this indicates that the presence of a lesion strongly favours SCE formation and that common fragile sites are probably chromosome regions preferentially damaged during the S phase.

Bromodeoxyuridine↗
PubMed1982

Cocultivation studies with cells of patients bearing fragile X chromosomes.

Fourteen cocultivation studies were carried out with cells of our patients with fragile X, one obligate and two possible female heterozygotes, two female controls, and a rabbit. In all cocultivations the number of fragile X chromosomes was sharply reduced in the patient cells. The strongest effect was causes by the animal cells. A distinct difference between the two controls in the reducing ability was observed. No such difference was found between the obligate and possible heterozygotes on the one hand and the controls on the other. To test the influence of the residual serum in the mixed blood cultures, the serum of a patient's blood sample was replaced by the serum of a control. The frequency of fragile X chromosomes was not decreased by this procedure. Therefore a soluble factor is supposed to exist which is produced by normal or heterozygote cells in culture and which reduces the expression of fragile sites in patient cells.

Animals↗
PubMed1983

[Prenatal diagnosis of a male fetal carrier of fragile X chromosome by the amniotic fluid cells].

A prenatal diagnosis of fragile X fra(X)(q28) has been performed in a pregnant woman obligate carrier of fra(X) by analysis of amniotic fluid cells taken by amniocentesis. The fra(X) has been observed in 30% (8/26) of the metaphases of the male fetus. These results were obtained within 10 days after amniocentesis using the in situ technique on cells grown first in Ham Medium supplemented with newborn calf serum and a serum substitute and changed for the last 19 hours with Tc 199 medium with 5% newborn calf serum and methotrexate (10 mg/l). This technique showed that fra(X) is not a clonal phenomenon and that its expression is related to the cell types and the origin of the studied cells.

Amniocentesis↗
PubMed1996

The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers.

A 200-300 kb region of chromosome 3p14.2, including the fragile site locus FRA3B, is homozygously deleted in multiple tumor-derived cell lines. Exon amplification from cosmids covering this deleted region allowed identification of the human FHIT gene, a member of ther histidine triad gene family, which encodes a protein with 69% similarity to an S. pombe enzyme, diadenosine 5', 5''' P1, P4-tetraphosphate asymmetrical hydrolase. The FHIT locus is composed of ten exons distributed over at least 500 kb, with three 5' untranslated exons centromeric to the renal carcinoma-associated 3p14.2 breakpoint, the remaining exons telomeric to this translocation breakpoint, and exon 5 within the homozygously deleted fragile region. Aberrant transcripts of the FHIT locus were found in approximately 50% of esophageal, stomach, and colon carcinomas.

Acid Anhydride Hydrolases↗