Matsuura S, Weemaes C, Smeets D, Takami H, Kondo N, Sakamoto S, Yano N, Nakamura A, Tauchi H, Endo S, Oshimura M, Komatsu K
Department of Radiation Biology, Hiroshima University, Japan.
Am J Hum Genet. 1997 Jun;60(6):1487-94. doi: 10.1086/515461.
Nijmegen breakage syndrome (NBS) is an autosomal recessive disorder characterized by microcephaly, short stature, immunodeficiency, and a high incidence of cancer. Cultured cells from NBS show chromosome instability, an increased sensitivity to radiation-induced cell killing, and an abnormal cell-cycle regulation after irradiation. Hitherto, patients with NBS have been divided into the two complementation groups V1 and V2, on the basis of restoration of radioresistant DNA synthesis, suggesting that each group arises from a different gene. However, the presence of genetic heterogeneity in NBS has been considered to be controversial. To localize the NBS gene, we have performed functional complementation assays using somatic cell fusion between NBS-V1 and NBS-V2 cells, on the basis of hyper-radiosensitivity, and then have performed a genomewide search for the NBS locus, using microcell-mediated chromosome transfer followed by complementation assays based on radiosensitivity. We found that radiation resistance was not restored in the fused NBS-V1 and NBS-V2 cells and that only human chromosome 8 complements the sensitivity to ionizing radiation, in NBS cell lines. In complementation assays performed after the transfer of a reduced chromosome, merely the long arm of chromosome 8 was sufficient for restoring the defect. Our results strongly suggest that NBS is a homogeneous disorder and that the gene for NBS is located at 8q21-24.
尼美根断裂综合征（NBS）是一种常染色体隐性疾病，其特征为小头畸形、身材矮小、免疫缺陷以及癌症高发。来自NBS患者的培养细胞表现出染色体不稳定、对辐射诱导的细胞杀伤敏感性增加以及辐射后细胞周期调控异常。迄今为止，根据辐射抗性DNA合成的恢复情况，NBS患者被分为两个互补组V1和V2，这表明每组源于不同的基因。然而，NBS中遗传异质性的存在一直存在争议。为了定位NBS基因，我们基于超辐射敏感性，利用NBS-V1和NBS-V2细胞之间的体细胞融合进行了功能互补分析，然后使用微细胞介导的染色体转移，随后基于辐射敏感性进行互补分析，对NBS基因座进行全基因组搜索。我们发现，融合的NBS-V1和NBS-V2细胞中的辐射抗性并未恢复，并且在NBS细胞系中，只有人类8号染色体能够弥补对电离辐射的敏感性。在转移一条减少的染色体后进行的互补分析中，仅8号染色体的长臂就足以修复缺陷。我们的结果强烈表明，NBS是一种同质疾病，并且NBS基因位于8q21-24。
