Atm knock-in mice harboring an in-frame deletion corresponding to the human ATM 7636del9 common mutation exhibit a variant phenotype
| Autor: | Kevin Spring, Cross S, Li C, Watters D, Ben-Senior L, Waring P, Ahangari F, Sl, Lu, Chen P, Misko I, Paterson C, Kay G, Ni, Smorodinsky, Shiloh Y, Mf, Lavin |
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| Předmět: |
Male
Mice Knockout Base Sequence Lymphoma Tumor Suppressor Proteins Apoptosis Cell Cycle Proteins Ataxia Telangiectasia Mutated Proteins DNA Thymus Neoplasms Protein Serine-Threonine Kinases Mice Mutant Strains Up-Regulation DNA-Binding Proteins Mice Inbred C57BL Ataxia Telangiectasia Mice Phenotype Mutagenesis Site-Directed Animals Humans Female Crosses Genetic Sequence Deletion |
| Zdroj: | Europe PubMed Central |
| Popis: | ATM, the gene mutated in the human immunodeficiency disorder ataxia-telangiectasia (A-T), plays a central role in recognizing ionizing radiation damage in DNA and in controlling several cell cycle checkpoints. We describe here a murine model in which a nine-nucleotide in-frame deletion has been introduced into the Atm gene by homologous recombination followed by removal of the selectable marker cassette by Cre-loxP site-specific, recombination-mediated excision. This mouse, Atm-DeltaSRI, was designed as a model of one of the most common deletion mutations (7636del9) found in A-T patients. The murine Atm deletion results in the loss of three amino acid residues (SRI; 2556-2558) but produces near full-length detectable Atm protein that lacks protein kinase activity. Radiosensitivity was observed in Atm-DeltaSRI mice, whereas the immunological profile of these mice showed greater heterogeneity of T-cell subsets than observed in Atm(-/-) mice. The life span of Atm-DeltaSRI mice was significantly longer than that of Atm(-/-) mice when maintained under nonspecific pathogen-free conditions. This can be accounted for by a lower incidence of thymic lymphomas in Atm-DeltaSRI mice up to 40 weeks, after which time the animals died of other causes. The thymic lymphomas in Atm-DeltaSRI mice were characterized by extensive apoptosis, which appears to be attributable to an increased number of cells expressing Fas ligand. A variety of other tumors including B-cell lymphomas, sarcomas, and carcinomas not seen in Atm(-/-) mice were observed in older Atm-DeltaSRI animals. Thus, expression of mutant protein in Atm-DeltaSRI knock-in mice gives rise to a discernibly different phenotype to Atm(-/-) mice, which may account for the heterogeneity seen in A-T patients with different mutations. |
| Databáze: | OpenAIRE |
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