Varon R, Reis A, Henze G, von Einsiedel H G, Sperling K, Seeger K
Institute of Human Genetics, Charité, Humboldt-University, 13353 Berlin, Germany.
Cancer Res. 2001 May 1;61(9):3570-2.
The Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive disorder associated with immune deficiency, chromosome fragility, and increased susceptibility to lymphoid malignancies. The aim of the present study was to elucidate the potential role of the gene mutated in NBS (NBS1) in the pathogenesis and disease progression of childhood acute lymphoblastic leukemia (ALL). Samples from 47 children with first relapse of ALL were analyzed for mutations in all 16 exons of the NBS1 gene, and in 7 of them (14.9%), four novel amino acid substitutions were identified. Mutations S93L, D95N, and I171V occur in the two known domains of nibrin that are probably involved in protein-protein interactions. Germ-line origin of the I171V mutation was confirmed in three patients, whereas the D95N exchange was present only in leukemic cells. The R215W mutation was observed in one ALL but also in a population-based study and probably represents a rare sequence variant. No additional mutations were found on the second allele in any of these seven patients. The observed NBS1 gene mutations in ALL patients points to its possible involvement in the pathogenesis of this disease.
奈梅亨断裂综合征（NBS）是一种罕见的常染色体隐性疾病，与免疫缺陷、染色体脆性以及对淋巴系统恶性肿瘤易感性增加有关。本研究的目的是阐明在NBS中发生突变的基因（NBS1）在儿童急性淋巴细胞白血病（ALL）发病机制和疾病进展中的潜在作用。对47例ALL首次复发患儿的样本进行NBS1基因全部16个外显子的突变分析，其中7例（14.9%）发现了4种新的氨基酸替换。突变S93L、D95N和I171V发生在可能参与蛋白质-蛋白质相互作用的已知尼布林两个结构域中。在3例患者中证实I171V突变源于种系，而D95N交换仅存在于白血病细胞中。在1例ALL患者以及一项基于人群的研究中均观察到R215W突变，其可能代表一种罕见的序列变异。在这7例患者中，任何一例的第二个等位基因均未发现其他突变。ALL患者中观察到的NBS1基因突变表明该基因可能参与了这种疾病的发病机制。
