Further delineation of the Nijmegen breakage syndrome

Abstract

We report on five independent families with a chromosome instability disorder that earlier had been called the Nijmegen breakage syndrome (NBS). These families, two from the Netherlands and three from Czechoslovakia, had a total of eight patients, five of whom are still alive. The main clinical manifestations were microcephaly, short stature, a "bird-like" face, immunological defects involving both the humoral and cellular system. In four of the five living patients it has been possible to study the chromosomes of cultured lymphocytes. The basic karyotype in these patients were normal, but in 17% to 35% of the metaphases rearrangements were found, preferentially involving chromosomes 7 and/or 14 at the sites 7p13, 7q34, and 14q11. The chromosomes of all five living patients were very sensitive to ionizing radiation. In addition, the DNA synthesis in their cultured lymphocytes and fibroblasts was more resistant to X-rays than in cells from controls. The NBS shares a number of important features with ataxia telangiectasia (AT). Both syndromes are characterized by the occurrence of typical rearrangements of chromosomes 7 and/or 14, cellular and chromosomal hypersensitivity to X-irradiation, radioresistance of DNA replication and immunodeficiency. However, there are also obvious differences: NBS patients have microcephaly but neither ataxia nor telangiectasia, and in contrast to the situation in AT the alpha-fetoprotein level in their serum is normal.

Nbs1 promotes ATM dependent phosphorylation events including those required for G1/S arrest

“…AT-5762ins137 and NBS cells show similar radiosensitivity, slightly less than A-T null lines ( Figure 1a) and similar defective S phase arrest (RDS response), equivalent to that seen in A-T null cells (Figure 1b). The results for CZD82CH are similar to those obtained with other NBS cell lines (Girard et al, 2000;Matsuura et al, 1998;Stewart et al, 1999;Taalman et al, 1989). G1/S phase arrest was examined using a fluorescent activated cell sorting (FACS) technique and an intermediate dose-dependent defect in G1/S arrest is evident in AT-5762ins137 and CZD82CH cells, which contrasts with the pronounced defect in AT5BI ( Figure 1c).…”

“…At the cellular level, NBS cell lines show many of the phenotypic abnormalities displayed by A-T including chromosomal instability and radiation sensitivity (Featherstone and Jackson, 1998). However, whilst NBS cells display an RDS phenotype that is similar to that shown by A-T (Taalman et al, 1989), they show little, if any, impairment in G1/S or G2/M phase arrest (Antoccia et al, 1997(Antoccia et al, , 1999Jongmans et al, 1997;Matsuura et al, 1998;Stewart et al, 1999;Yamazaki et al, 1998) suggesting either that NBS1 is not required for these latter two checkpoints or that there is some level of redundancy. Additionally, radiation-induced activation of ATM kinase as well as the phosphoryla-tion of certain ATM dependent substrates (e.g.…”

A Quantitative Measurement of the Human Somatic Mutation Rate

“…Remarkably, in Nijmegen breakage syndrome, l is almost normal. In this condition, rearrangements of chromosomes 7 and 14 are common, and even more frequent than in ataxiatelangiectasia (44)(45)(46). Perhaps in the pathogenesis of malignancy in Nijmegen breakage syndrome, chromosomal rearrangements are more important, and point mutations that inactive genes such as PIG-A occur at a normal rate.…”

Progressive vitiligo, mental retardation, facial dysmorphism, and urethral duplication without chromosomal breakage or immunodeficiency.

“…Finally, the diagnosis of Nijmegen breakage syndrome was suspected since it includes most of the clinical manifestations of this patient.9 10 However, the lack of serious infections and of chromosomal abnormality strongly argues against this diagnosis. Therefore, our patient seems to have a syndrome different from previously reported neurocutaneous syndromes and from the chromosomal breakage syndromes.…”