Nijmegen breakage syndrome (NBS) is a rare autosomal receSSIve chromosomeinstability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition, with cellular features similar to that of ataxia telangiectasia (AT). NBS results from mutations in the mammalian gene Nbs] that codes for a 95-kDa protein called nibrin, NBSI, or p95. To establish an animal model for NBS, we attempted to generate NBS I knockout mice. However, NBS I gene knockouts were

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... at an early embryonic stage. NBSI homozygous (-I-) blastocyst cells cultured in vitro showed retarded growth and subsequently underwent growth arrest within 5 days of culture. Apoptosis, assayed by TUNEL staining, was observed in NBSI homozygous (-I-) blastocyst cells cultured for four days. NBSI heterozygous(+I-) mice were normal, and exhibited no specific phenotype for at least one year. However, fibroblast cells from NBSI heterozygous(+I-) mice displayed an enhanced frequency of spontaneous transformation to anchorage-independent growth as compared to NBSI wild-type(+I+) cells. Furthermore, heterozygous(+I-) mice exhibited a high incidence of hepatocellular carcinoma after one year compared to wild-type mice, even though no significant differences in the incidence of other tumors such as lung adenocarcinoma and lymphoma were observed. Taken together, these results strongly suggest that NBSI heterozygosity and reduced NBS I expression induces formation of specific tumors in mice.