Molecular study on Nijmegen breakage sybdrome

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ATM underlying gene for Ataxia Telangiectasia, is still mysterious for the phenotypic expression of AT and AT Iike gene could be helpful to understand this mechanism. Nijmegen Breakage Syndrome (NBS) has quite different clinical features from AT,since patients with NBS do not show elevation of alpha-fetoprotein, cerebellar ataxia, or telangiectasia but do have microcephaly and growth retardation. However, the cell-biological findings, such as chromosome instability, increased radiation sensitivity and abnormal cell cycle check point, resemble those in AT,suggesting that the same pathway is impaired in both syndromes.Similarity between NBS and AT was observed in p53 induction after irradiation. Although the induction of p53 was dose-dependent, the onset of induction was delayd and the maximum p53 at several hrs after irradiation was lower than that of normal cells. Consequently, p53 induction in NBS Iymphoblasts was intermediate between normal cells and AT cells, and this corresponds to a mild radiation sensitivity of NBS to cell killing in comparison with AT cells. However, different underlying genes for NBS and AT were confirmed by complementation assay using fused cells with NBS cells and AT cells. To identify the chromosome carrying NBS gene, we introduced a single human chromosome or their fragments into NBS established cells through microcell and assayd the complementation based on radiation sensitivity. Only hybrid cells containing a human chromosome region 8q21-23 was restored the radiation resistance. Furtermore, the haploid DNA analysis of a patient family with consanguinity strongly suggests the 1-2 cM DNA region around D8S1811 as the candidate locus.These results are useful information for the next step of gene cloning and understanding of AT-Iike gene function.