A targeted mouse Brca1 mutation removing the last BRCT repeat results in apoptosis and embryonic lethality at the headfold stage

A mouse model with a targeted mutation in the 3' end of the endogenous Brca 1 gene, Brca1(1700T), was generated to compare the phenotypic consequences of truncated SI cal proteins with other mutant Brca1 models reported in the literature to date. Mice heterozygous for the Brca1(1700T) mutation do not show any predisposition to tumorigenesis, Treatment of these mice with ion izing radiation or breeding with Ape, Msh-2 or Tp53 mutant mouse models did not show any change in the tumor phenotype, Like other Brca1 mouse models, the Brca1(1700T) mutation is embryonic lethal in homozygous state, However , homozygous Brca1(1700T) embryos reach the headfold stage but are delayed in their development and fail to turn. Thus, in contrast to Brca1(null) mod els, the mutant embryos do not undergo growth arrest leading to a developme ntal block at 6.5 dpc, but continue to proliferate and differentiate until 9.5 dpc. Homozygous embryos die between 9.5-10.5 dpc due to massive apoptos is throughout the embryo. These results indicate that a C-terminal truncati ng Brca1 mutation removing the last BRCT repeat has a different effect on n ormal cell function than does the complete absence of Brca1.