Abstract
A mouse model with a targeted mutation in the 3′ end of the endogenous Brca1 gene, Brca11700T, was generated to compare the phenotypic consequences of truncated Brca1 proteins with other mutant Brca1 models reported in the literature to date. Mice heterozygous for the Brca11700T mutation do not show any predisposition to tumorigenesis. Treatment of these mice with ionizing radiation or breeding with Apc, Msh-2 or Tp53 mutant mouse models did not show any change in the tumor phenotype. Like other Brca1 mouse models, the Brca11700T mutation is embryonic lethal in homozygous state. However, homozygous Brca11700T embryos reach the headfold stage but are delayed in their development and fail to turn. Thus, in contrast to Brca1null models, the mutant embryos do not undergo growth arrest leading to a developmental 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 apoptosis throughout the embryo. These results indicate that a C-terminal truncating Brca1 mutation removing the last BRCT repeat has a different effect on normal cell function than does the complete absence of Brca1.
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Acknowledgements
The authors would like to thank Shantie Jagmohan-Changur, Ron Smits, Heleen van der Klift, and Nandy Hofland for technical assistance and critical reading of the manuscript.
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Hohenstein, P., Kielman, M., Breukel, C. et al. A targeted mouse Brca1 mutation removing the last BRCT repeat results in apoptosis and embryonic lethality at the headfold stage. Oncogene 20, 2544–2550 (2001). https://doi.org/10.1038/sj.onc.1204363
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DOI: https://doi.org/10.1038/sj.onc.1204363
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