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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new fluorescence plus Giemsa staining technique now makes the detection of sister-chromatid exchange (SCE) a relatively easy matter in cells containing 5-BrdU-substituted DNA. The technique has been applied to human cells to examine the distribution of SCE between different people and within different chromosomes. The results show: (1) That there were no large differences in the incidence of SCE between blood leukocyte chromosomes from male and female adults and newborn, and that similar frequencies were found in cells from two patients with ataxia telangiectasia which, nevertheless, showed the typical increases in chromosomal aberrations. (2) The distribution of SCE between chromosomes in the complement was found to be proportional to chromosome length, although the smaller chromosomes were under-represented, but not significantly so. (3) The distribution of SCE within chromosomes was nonrandom, with a deficiency in the centromeric and an excess in the mid-arm regions. There was no evidence for an excess of SCE in chromosome regions rich in AT DNA sequences. (4) The frequency of SCE is to some extent dependent of 5-BrdU concentration, but the influence of concentration is minimal within the range of from 1 to 160 muM. Human cells exposed over two cell cycles at these higher BrdU levels have around 14 SCE per cell-a frequency virtually identical with that observed in cultured cells from the Chinese hamster, wallaby, and rat kangaroo.
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PMID:Sister chromatid exchange in human chromosomes from normal individuals and patients with ataxia telangiectasia. 5 31

Ataxia-telangiectasia (AT) is a heterogeneous autosomal recessive disorder marked by cerebellar ataxia, oculocutaneous telangiectases, hypersensitivity to ionizing radiation, immunodeficiency, and cancer susceptibility. AT is also a spontaneous chromosomal breakage syndrome, notable for tissue-specific cytogenetic changes and telomeric fusions. Molecular characterization of rearrangements specific to T-lymphocytes suggests that a DNA repair/processing defect is potentially responsible for the diverse array of chromosomal abnormalities observed in a variety of AT cell types.
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PMID:The cytogenetics of ataxia telangiectasia. 175 58

The leukemic cells and derivative cell line from a 74-year-old male with T-cell acute lymphoblastic leukemia showed chromosomal abnormalities including a t(14;14)(q11.2;q32). This translocation is characteristic of a variety of T-cell malignancies, particularly T-cell prolymphocytic leukemia and the clonal proliferations of peripheral T cells in patients with ataxia-telangiectasia. Using DNA probes that spanned the T-cell receptor alpha chain (TCRA) joining (J) locus, the DNA rearrangement caused by the translocation was identified, cloned, and sequenced. The breakpoint shows site-specific juxtaposition of a TCRA joining segment and DNA from a region of 14q32 centromeric to the immunoglobulin heavy chain locus. Comparison of restriction map and nucleotide sequence from this translocation with other related chromosomal breakpoints suggests a dispersion of breakpoints throughout the 14q32 region.
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PMID:Characterization of the breakpoint of a t(14;14)(q11.2;q32) from the leukemic cells of a patient with T-cell acute lymphoblastic leukemia. 196 57

We have studied the segregation of an RFLP detected with a human ETS-1 genomic probe in 25 families containing members affected with ataxia-telangiectasia (AT) and in 27 families from the Centre d'Etude du Polymorphisme Humain (CEPH) panel. We have recently mapped a gene for AT to 11q22-23 by linkage to the markers THY1 and D11S144. Multipoint linkage analysis of the CEPH families indicated that ETS-1 is located on chromosome 11q approximately 19.2 centimorgans telomeric to THY1. Analysis of the segregation of ETS-1 alleles in AT families yields strongly negative LOD scores, excluding an AT gene from a region extending 15 cM to either side of ETS-1. Multipoint mapping of ETS-1, D11S144, THY1, and AT also excludes the possibility that an AT gene is telomeric to ETS-1.
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PMID:The ataxia-telangiectasia gene (ATA) on chromosome II is distinct from the ETS-1 gene. 196 27

We recently mapped the gene for ataxia-telangiectasia group A (ATA) to chromosome 11q22-23 by linkage analysis, using the genetic markers THY1 and pYNB3.12 (D11S144). The most likely order was cent-AT-S144-THY1. The present paper describes further mapping of the AT locus by means of a panel of 10 markers that span approximately 60 cM in the 11q22-23 region centered around S144 and THY1. Location scores indicate that three contiguous subsegments within the [S144-THY1] segment, as well as three contiguous segments telomeric to THY1, are each unlikely to contain the AT locus, while the more centromeric [STMY-S144] segment is most likely to contain the AT locus. These data, together with recent refinements in the linkage and physical maps of 11q22-23, place the AT locus at 11q23.
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PMID:Further mapping of an ataxia-telangiectasia locus to the chromosome 11q23 region. 222 Aug 26

Two breakpoints within chromosome 11q23 were characterized with 29 DNA probes to establish a physical map of the region. This region is notable in that it contains at least 14 functional genes which are also syntenic in the mouse (chromosome 9). Chromosome 11q23 includes these markers: STMY, CLG, NCAM, DRD2, APOA1, APOC3, APOA4, CD3E, CD3D, CD3G, PBGD, THY1, ets-1, and cbl-2. The two breakpoints, herein called "X;11" and "4;11," defined a region of approximately 8 cM containing the APO and CD3 complexes as well as the polymorphic marker D11S29. DRD2 localized centromeric to the X;11 breakpoint despite evidence for close genetic linkage to D11S29, suggesting that DRD2 lies close to the X;11 breakpoint. THY1, PBGD, and cbl-2 localized telomeric to the 4;11 breakpoint and thus to the [D11S29--APO--CD3] grouping as well. The physical map helps to correlate the cytogenetic and linkage maps of this region. It also suggests that the human 11q23 syntenic grouping is inverted with respect to its murine counterpart. Based on this physical map and on our primary linkage map of the 11q23 region, we are able to confirm a preliminary localization of the gene for ataxia-telangiectasia group A (ATA) to a region centromeric to the interval defined by D11S144 (pYNB3.12) and THY1.
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PMID:Physical mapping of the human chromosome 11q23 region containing the ataxia-telangiectasia locus. 233 77

Ataxia telangiectasia (A-T) is an autosomal recessive disorder characterised by progressive neurological degeneration, oculocutaneous telangiectasia, immunodeficiency and a high incidence of lymphoid tumours. A prerequisite to gaining a complete understanding of the basic defect that results in these features is the localization of the gene(s) involved. We report here a linkage analysis using seven polymorphic markers, which map to 11q22-23, on a sample of 35 consecutively obtained families from the British Isles showing this disorder. In a pairwise analysis, the strongest support for linkage was a lod score of 4.01 at zero recombination from Thy-1. This result supports a previous report showing linkage of the A-T gene to 11q22-23. We have also obtained evidence in a multipoint analysis for a more centromeric A-T-linked locus in the region between YNB 3.12/CJ52.208 and 2-7-1D6. This observation is also supported by inspection of the haplotypes of selected recombinants.
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PMID:Analysis of 7 polymorphic markers at chromosome 11q22-23 in 35 ataxia telangiectasia families; further evidence of linkage. 237 52

Various cellular defects have been found in ataxia telangiectasia (A-T) cells including increased radiosensitivity, increased sensitivity to various chemical agents, a probable DNA repair defect and a defect in DNA synthesis. How these different features are related to each other is at present unknown. It has been suggested that there is a defect in A-T that acts in tissue differentiation as well as during growth and in the mature adult. This hypothesis is supported by the observations, for example, of an immature thymus present in patients, the production of alpha-fetoprotein, which results in a high serum level, and ovarian dysgenesis. A gene for A-T has recently been localized to chromosome region 11q22-23, a site involved in chromosomes translocations in some non-lymphoid leukaemias. At the chromosomal level the spontaneous abnormalities in A-T include, first, an increased frequency of cells showing chromosome translocations involving immune system genes that normally undergo rearrangement to form a functional product; secondly, the formation of telometric dicentrics in both lymphocytes and fibroblasts; and thirdly formation of long-lived chromosome damage following exposure to ionizing radiation and radiomimetic drugs. The gene defect underlying this disorder is unknown and distinguishing between primary and secondary effects of the mutant gene is difficult. We consider alternative models for retention of translocation T cells. First, it is possible that there is a defect in recognition of site-specific damage leading to retention of translocation cells that might otherwise be removed. Secondly, a feature common to the production of illegitimate T-cell receptor gene rearrangements and to formation of telomeric dicentric chromosomes in A-T cells is an increased period of time available for chromosome interchange, possibly due to a site-specific defect in strand break repair. It is possible that this defect may also prevent chromosome restitution following exposure of cells to ionizing radiation.
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PMID:Increased radiosensitivity and the basic defect in ataxia telangiectasia. 257 63

We have detected and cloned two rearrangements in the T-cell receptor alpha locus from a clone of somatic cell hybrids carrying a t(14;14)(q11;q32) chromosomal translocation derived from an ataxia telangiectasia patient with T-cell chronic lymphocytic leukemia. The T-cell clone carrying the t(14;14) chromosomal translocation was known to be present for greater than 10 years before the onset of overt leukemia. One molecular rearrangement of the T-cell receptor alpha locus corresponded to a functional variable-joining region (V-J) joining, whereas the other derived from the breakpoint of the t(14;14)(q11;q32) translocation. Chromosomal in situ hybridization of the probe derived from the t(14;14) breakpoint localized the breakpoint region to 14q32.1, apparently the same region that is involved in another ataxia telangiectasia characteristic chromosome translocation, t(7;14)(q35;q32). The 14q32.1 breakpoint is at least 10,000 kilobase pairs (kbp) centromeric to the immunoglobulin heavy chain locus. Sequence analysis of the breakpoint indicates the involvement of a J alpha sequence during the translocation. Comigration of high-molecular weight DNA fragments involved with t(7;14) and t(14;14) translocations suggests the presence of a cluster of breakpoints in the 14q32.1 region, the site of a putative oncogene, TCL1.
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PMID:Molecular analysis of a t(14;14) translocation in leukemic T-cells of an ataxia telangiectasia patient. 278 89

T-cell tumors are characterized by inversions or translocations of chromosome 14. The breakpoints of these karyotypic abnormalities occur in chromosome bands 14q11 and 14q32--the same bands in which the T-cell receptor (TCR) alpha-chain and immunoglobulin heavy chain genes have been mapped, respectively. Patients with ataxia-telangiectasia are particularly prone to development of T-cell chronic lymphocytic leukemia with such chromosomal abnormalities. We now describe DNA rearrangements of the TCR alpha-chain gene in an ataxia-telangiectasia-associated leukemia containing both a normal and an inverted chromosome 14. The normal chromosome 14 has undergone a productive join of TCR alpha-chain variable (V alpha) and joining (J alpha) gene segments. The other allele of the TCR alpha-chain gene features a DNA rearrangement, about 50 kilobases from the TCR alpha-chain constant (C alpha) gene, that represents the breakpoint of the chromosome 14 inversion; this breakpoint is comprised of a TCR J alpha segment (from 14q11) fused to sequences derived from 14q32 but on the centromeric side of C mu. These results imply that 14q32 sequences located at an undetermined distance downstream of the immunoglobulin C mu locus can contribute to the development of T-cell tumors.
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PMID:The breakpoint of an inversion of chromosome 14 in a T-cell leukemia: sequences downstream of the immunoglobulin heavy chain locus are implicated in tumorigenesis. 312 10


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