This Bap1 (Brca1 associated protein 1) zinc finger nuclease mediated mutant strain exhibits increased sensitivity to asbestos and accelerated onset of asbestos-induced malignant mesothelioma.
Joseph R. Testa, Fox Chase Cancer Center
The ubiquitin carboxy-terminal hydrolase encoded by the Bap1, Brca1 associated protein 1, gene is involved in the regulation of histone ubiquitination and cell growth. Mutations in this gene have been associated with tumor predisposition syndrome. Somatic mutations of the BAP1 gene have been found in malignant mesothelioma, uveal melanoma, atypical Spitz tumors, cutaneous melanoma, and intrahepatic cholangiocarcinomas. These mice carry a zinc finger nuclease (ZFN) mediated deletion of exons 6 and 7 of the Bap1 gene. Homozygotes are embryonic lethal, dying at E7.5 to E8.5. Heterozygous mice exhibit accelerated onset of asbestos-induced malignant mesothelioma, developing abdominal swelling as early as 20 weeks of age after induction, compared to the 27 weeks of age observed in controls. Median survival of heterozygotes is 43 weeks after initial exposure (intraperitoneal injection of asbestos fibers) compared to 55 weeks median survival of wildtype mice. Mutant heterozygous mice, up to 12 months of age, generally do not develop tumors. Spontaneous tumors were found in ~58% of heterozygous mice compared to ~9% of wild type mice. The median age of detection of tumors in heteroygotes is 19.7 months, with ovarian sex cord stromal tumors being the predominant tumor type, and with ~63% of females developing these tumors. Lung adenocarcinomas, mammary gland carcinomas, and spindle cell tumors of the skin were also common. There was one report of a heterozygous mouse developing a spontaneous mesothelioma.
Zinc finger nuclease (ZFN) editing induced the deletion of exons 6 and 7 in the Bap1 gene. ZFN mRNA was injected into FVB oocytes. Founder mice were maintained on the FVB background. Upon arrival, sperm was cryopreserved. To establish a live colony, an aliquot of frozen sperm was used to fertilize C57BL/6J oocytes (Stock No. 000664).
|Allele Name||endonuclease-mediated mutation 1, Joseph R Testa|
|Allele Type||Endonuclease-mediated (Null/Knockout)|
|Gene Symbol and Name||Bap1, Brca1 associated protein 1|
|Strain of Origin||FVB|
|Molecular Note||Zinc finger nuclease mediated targeted mutation deleted exons 6 and 7.|
When maintaining a live colony, heterozygous mice may be bred together, to wildtype siblings, or to FVB/NJ inbred mice (Stock No. 001800). Homozygotes are embryonic lethal.
When using the Bap1 KO mouse strain in a publication, please cite the originating article(s) and include JAX stock #028905 in your Materials and Methods section.