Nijmegen breakage syndrome.

Burgt, C.J.A.M. van der; Chrzanowska, K; Smeets, D.F.C.M.; Weemaes, C.M.R.

doi:10.1136/jmg.33.2.153

Cited by 218 publications

(113 citation statements)

References 19 publications

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“…8 In 40% of the patients, in fact, a malignancy occurs before the age of 21. 9 About 90% of the NBS patients are of Slav origin and carry the major founder mutation 657del5 in exon 6; eight distinct mutations have been found in families of different ethnic origin. 10 -12 In NBS cells, chromatid and chromosome breakages, acentric fragments, asymmetrical multiradial configurations among nonhomologous chromosomes and sporadic or clonal translocations and inversions are present.…”

Section: Introductionmentioning

confidence: 99%

Chromosome instability and nibrin protein variants in NBS heterozygotes

et al. 2003

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The frequency of spontaneous chromosome abnormalities in peripheral blood lymphocytes and the X-ray G2 sensitivity in lymphoblastoid cell lines (LCL) have been evaluated in heterozygous subjects from three unrelated Nijmegen Breakage Syndrome (NBS) families, characterised by different mutations in the NBS1 gene. In all the 13 NBS heterozygotes analysed, we found spontaneous chromosome instability consisting in chromosome and chromatid breakages and rearrangements, while radiosensitivity was similar to that of control LCLs in seven out of eight tested NBS heterozygotes. The densitometric analysis of nibrin by immunoblotting indicated only a slight reduction in some of the LCLs from NBS carriers, whereas the immunoprecipitation assay appears a more reliable tool to detect NBS carriers. By means of immunoprecipitation, we investigated two homozygous and four heterozygous subjects. In the cells of the NBS patient 668, with the mutation 900del25, an alternative form of nibrin with a molecular weight of approximately 55 kDa has been detected. This variant protein, together with the normal p95, was also found in the LCL 34 established from a carrier of the same family. Signals of nibrin with a molecular weight lower than 95 kDa, but higher than that observed in LCLs 668 and 34, were detected also in three carriers from the family with mutation 835del4.

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Section: Introductionmentioning

confidence: 99%

Chromosome instability and nibrin protein variants in NBS heterozygotes

et al. 2003

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“…1,2 Due to the overlap of clinical and cellular features of patients with ataxia telangiectasia (AT), NBS was described as an AT variant syndrome until the underlying gene product mutation was identified. [3][4][5] Cells from both AT and NBS patients show increased sensitivity to ionizing radiation (IR), genomic instability and cell cycle checkpoint defects following DNA damage, 6,7 suggesting that both gene products participate in the same DNA damage response pathway.…”

Section: Introductionmentioning

confidence: 99%

The NBS1-ATM Connection Revisited

Difilippantonio

Nussenzweig²

2007

Cell Cycle

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Nijmegen Breakage syndrome (NBS) is a rare autosomal recessive disorder characterized by microcephaly, immunodeficiency, and increased predisposition to the development of malignancy. 1,2 Due to the overlap of clinical and cellular features of patients with ataxia telangiectasia (AT), NBS was described as an AT variant syndrome until the underlying gene product mutation was identified. 3-5 Cells from both AT and NBS patients show increased sensitivity to ionizing radiation (IR), genomic instability and cell cycle checkpoint defects following DNA damage, 6,7 suggesting that both gene products participate in the same DNA damage response pathway. Here we highlight recent developments and refinements in our understanding of the interplay between NBS1 and ATM in vivo.

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“…NBS cells cultured in vitro are deficient in the response to treatment with DNA DSB-inducing agents such as ionizing radiation and radiomimetic compounds. These defective responses include reduction in colony-forming ability post-irradiation, a failure to inhibit DNA synthesis in response to acute doses of radiation, and an increased frequency of chromosomal aberrations (4,5). Positional cloning studies in NBS families and functional complementation studies identified a single gene, NBS1, which is mutated in most patients with NBS (6,7).…”

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Importin KPNA2 Is Required for Proper Nuclear Localization and Multiple Functions of NBS1

Tseng

Chang

Wu³

et al. 2005

Journal of Biological Chemistry

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Nijmegen breakage syndrome (NBS) is a chromosomal-instability syndrome associated with cancer predisposition, radiosensitivity, microcephaly, and growth retardation. The NBS gene product, NBS1, is a component of the MRE11-RAD50-NBS1 (MRN) complex, a central player associated with double strand break (DSB) repair. In response to radiation, NBS1 is phosphorylated by ATM, and the MRN complex relocalizes to form punctate nuclear foci for DNA repair. NBS1 controls both the nuclear localization of the MRN complexes and radiation-induced focus formation. We report here that the KPNA2 (importin ␣1) is important for the normal nuclear localization of the MRN complex and its proper formation of the nuclear foci. KPNA2 is the only member of the importin ␣ family that physically interacts with NBS1, and the KPNA2-mediated nucleus localization sequence (NLS) is mapped to amino acid residues 461-467 of NBS1 that is sufficient for both the interaction with KPNA2 and the proper nuclear localization. Inhibition of KPNA2 or blockage of the KPNA2 interaction with NBS1 results in a reduction of radiation-induced nuclear focus accumulation, DSB repair, and cell cycle checkpoint signaling of NBS1. Collectively, our results strongly suggest that an interaction with KPNA2 contributes to nuclear localization and multiple tumor suppression functions of the NBS1 complex.

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Nijmegen breakage syndrome.

Cited by 218 publications

References 19 publications

Chromosome instability and nibrin protein variants in NBS heterozygotes

Chromosome instability and nibrin protein variants in NBS heterozygotes

The NBS1-ATM Connection Revisited

Importin KPNA2 Is Required for Proper Nuclear Localization and Multiple Functions of NBS1

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