Cancer incidence in Nijmegen breakage syndrome is modulated by the amount of a variant NBS protein
Cancer incidence in Nijmegen breakage syndrome is modulated by the amount of a variant NBS protein
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DOI：
10.1093/carcin/bgl126
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发表时间：
2007-01-01
期刊：
影响因子：
4.7
通讯作者：
Digweed, Martin
中科院分区：
文献类型：
--
作者：
Krueger, Lars;Demuth, Ilja;Digweed, Martin
奈亨破裂综合征（NBS）是一种人类遗传疾病，其特点是放射敏感性、免疫缺陷和癌症风险增加，特别是b细胞非霍奇金淋巴瘤。NBS1基因编码一种蛋白质，nibrin，参与DNA双链断裂的加工/修复和细胞周期检查点。大多数患者是纯合子的创始突变，一个5bp的缺失。这种突变实际上是次胚性的，因为通过交替翻译产生了一个功能相关的截断蛋白，长度约为70 kDa。同源基因在小鼠体内的零突变是致命的；然而，携带创始突变的人NBS1 cDNA可以拯救小鼠的零突变细胞。显然，截断的p70-nibrin能够维持全长蛋白的重要细胞功能。我们使用半定量免疫沉淀法检测了来自NBS患者的26个淋巴母细胞样b细胞系的p70-nibrin表达水平，并将其与两个贡献中心提供的临床表型细节相关联。我们发现来自不同患者的细胞系中p70-nibrin的数量有相当大的差异。临床病史检查显示p70-nibrin表达水平与淋巴瘤发病率有明显的统计学意义。患者之间p70-nibrin水平的差异可能反映了替代翻译过程对其他遗传和非遗传因素的易感性。与细胞中p70-nibrin水平较低的患者相比，细胞中能够维持特别高水平的截断p70-nibrin蛋白的患者患淋巴瘤的风险较低。
The human genetic disorder, Nijmegen breakage syndrome (NBS), is characterized by radiosensitivity, immunodeficiency and an increased risk for cancer, particularly B-cell non-Hodgkin lymphoma. The NBS1 gene codes for a protein, nibrin, involved in the processing/repair of DNA double-strand breaks and in cell cycle checkpoints. The majority of patients are homozygous for a founder mutation, a 5 bp deletion. This mutation is actually hypomorphic, since a functionally relevant truncated protein, of similar to 70 kDa, is produced by alternative translation. Null mutation of the homologous gene in mice is lethal; however, null-mutant murine cells can be rescued by a human NBS1 cDNA carrying the founder mutation. Clearly, the truncated p70-nibrin is able to sustain vital cellular functions of the full-length protein. We have used semi-quantitative immunoprecipitation to examine a panel of 26 lymphoblastoid B-cell lines from NBS patients for their level of p70-nibrin expression and correlate this with details of clinical phenotype provided by the two contributing centres. We find considerable variation in the amount of p70-nibrin in cell lines from different patients. Examination of clinical history indicated a clear and statistically significant correlation between p70-nibrin expression levels and lymphoma incidence. The variation in p70-nibrin levels between patients probably reflects the susceptibility of the alternative translation process to other genetic and non-genetic factors. Patients whose cells are able to maintain particularly high levels of the truncated p70-nibrin protein are at a lower risk for lymphoma than those patients with low levels of p70-nibrin in their cells.