Increased Levels of Mutagen-Induced Chromosome Breakage in Down Syndrome Children with Malignancy
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Keywords:
Trisomy
Nijmegen breakage syndrome
Abnormality
Abstract Prenatal diagnosis was performed in two pregnancies at risk of the Nijmegen breakage syndrome. In one pregnancy, an affected fetus was diagnosed by demonstration of radioresistant DNA synthesis, using autoradiographic detection of incorporated tritiated thymidine in cultured chorionic villus cells. The diagnosis was confirmed in fetal skin fibroblasts. In the other case, the fetus appeared unaffected. Using the same procedure, unaffected fetuses were predicted from chorionic villus cells in two pregnancies at risk of ataxia telangiectasia, which is another genetic disorder showing the feature of radioresistant DNA synthesis. The present biochemical method for prenatal detection of Nijmegen breakage syndrome and ataxia telangiectasia can be used as a simplified alternative to the cytogenetic procedures reported earlier for ataxia telangiectasia.
Nijmegen breakage syndrome
Chorionic villi
Chorionic villus sampling
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Nijmegen breakage syndrome
Microcephaly
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Nijmegen breakage syndrome is characterized by a variable T cell and B cell immunodeficiency, growth failure, and an increased risk of malignancy. It is inherited in an autosomal recessive manner and is biochemically related to ataxia-telangiectasia. Cells from a patient with Nijmegen breakage syndrome were unable to arrest cell cycle progression after exposure to ionizing radiation, and BrdU incorporation into newly synthesized DNA was uninhibited, demonstrating that these cells have an aberrant response to radiation exposure. Although gross chromosomal breakage was observed, dinucleotide repeat segments were stable over time, suggesting that other types of DNA stability were not affected. DNA-PK activity, which is mediated by a protein related to the ataxia-telangiectasia gene product and is intimately involved in DNA repair and VDJ recombination, was normal in cells from an NBS patient. Therefore, cells from patients with Nijmegen breakage syndrome have an abnormal response to radiation exposure similar to that seen in ataxia-telangiectasia.
Nijmegen breakage syndrome
Chromosome instability
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Nijmegen breakage syndrome
Chromosome instability
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Ataxia telangiectasia (AT) and Nijmegen breakage syndrome (NBS) are rare autosomal recessive conditions caused by mutations in respectively ATM and NBS1. The encoding proteins ATM and nibrin are involved in the processing of DNA damage and maintenance of genomic stability. Ataxia telangiectasia is described. Hallmarks are cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, radiation sensitivity and predispostion to cancer. A new double missense mutation in the ATM gene in a Dutch family is reported. Two young adult brothers with AT are described with only minor cerebellar ataxia. Their most striking symptom was a resting tremor. Four adult onset AT patients are described lacking pronounced cerebellar atrophy but displaying severe spinal muscular atrophy. In the patients the ATM function, as measured by the p53 response, was close to normal. Nijmegen breakage syndrome is described extensively. Characteristics are microcephaly, typical facial appearance, immunodeficiency, chromosomal instability, X-ray hypersensitivity, and predisposition to cancer. The immunological findings in a large series of NBS patients are reported. IgA, IgG and IgG2 levels were decreased in most patients, while IgM levels were normal or even slightly increased. The data suggest a defective class switching in NBS. A neuropathological study in NBS is described. Severe microcephaly with a simplified gyral was found. The number of cortical neurons was clearly diminished. A role of NBS1 in corticogenesis is suggested. A patient with the NBS phenotype is described without a mutation in NBS1. The distinct neurological features of AT and NBS are likely to be due to different roles of ATM and nibrin in the nervous system. Nibrin seems to be particularly important for the development of the nervous system, while ATM seems to play a more maintaining role. The similarities on the laboratory level between the two disorders seem to be the result of functional links between the two proteins.
Nijmegen breakage syndrome
Microcephaly
Cerebellar ataxia
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Nijmegen breakage syndrome
Rad50
Bloom syndrome
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Cultured cells from patients with ataxia telangiectasia (AT) or Nijmegen breakage syndrome (NBS) are hypersensitive to ionizing radiation. After radiation exposure, the rate of DN A replication is inhibited to a lesser extent than in normal cells, whereas the frequency of chromosomal aberrations is enhanced. Both of these features have been used in genetic complementation studies on a limited series of patients. Here we report the results of extended complementation studies on fibroblast strains from 50 patients from widely different origins, using the radioresistant DNA replication characteristic as a marker. Six different genetic complementation groups were identified. Four of these, called AB, C, D, and E (of which AB is the largest), represent patients with clinical signs of AT. Patients having NBS fall into two groups, VI and V2. An individual with clinical symptoms of both AT and NBS was found in group V2, indicating that the two disorders are closely related. In AT, any group-specific patterns with respect to clinical characteristics or ethnic origin were not apparent. In addition to the radiosensitive ATs, a separate category of patients exists, characterized by a relatively mild clinical course and weak radiosensitivity. It is concluded that a defect in one of at least six different genes may underlie inherited radiosensitivity in humans. To facilitate research on defined defects, a complete list of genetically characterized fibroblast strains is presented.
Nijmegen breakage syndrome
Radiosensitivity
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We used a modified colony survival assay to measure the sensitivity to ionizing radiation of more than 50 lymphoblastoid cell lines from normal individuals and from patients with ataxia-telangiectasia, Nijmegen breakage syndrome variants, and X-linked agammaglobulinemia. All of these disorders are associated with an increased frequency of cancer. Lymphoblastoid cell lines from patients with ataxia-telangiectasia complementation groups A, C, D, and E; ATFresno; Nijmegen breakage syndrome variants V1 and V2; and X-linked agammaglobulinemia showed marked radiosensitivity, whereas ataxia-telangiectasia heterozygotes were similar to controls. Friedreich's ataxia is not associated with increased cancer risk; lymphoblastoid cell lines from two such patients showed normal radiosensitivity. Taken together, these results suggest that some forms of X-ray sensitivity and cancer susceptibility share a common mechanism, such as an enzyme that is necessary both for the repair of radiation damage to DNA and for gene rearrangements during V(D)J recombination.
Nijmegen breakage syndrome
Radiosensitivity
Lymphoblast
Radiation sensitivity
Heterozygote advantage
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Nijmegen breakage syndrome
Radioresistance
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