Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive human diseas e whose clinical features include growth retardation, immunodeficiency, and increased susceptibility to lymphoid malignancies. Cells from NBS patients exhibit gamma -irradiation sensitivity, S-phase checkpoint defects, and ge nomic instability. Recently, it was demonstrated that this chromosomal brea kage syndrome is caused by mutations in the NBS1 gene that result in a tota l loss of full-length NBS1 expression [1, 2], Here we report that in contra st to the viability of NBS patients, targeted inactivation of NBS1 in mice leads to early embryonic lethality in utero and is associated with poorly d eveloped embryonic and extraembryonic tissues. Mutant blastocysts showed gr eatly diminished expansion of the inner cell mass in culture, and this find ing suggests that NBS1 mediates essential functions during proliferation in the absence of externally induced damage. Together, our results indicate t hat the complex phenotypes observed in NBS patients and cell lines may not result from a complete inactivation of NBS1 but may instead result from hyp omorphic truncation mutations compatible with cell viability.