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Atm Knock-in Mice Harboring an In-frame Deletion Corresponding to the Human ATM 7636del9 Common Mutation Exhibit a Variant Phenotype¹

Queensland Cancer Fund Research Laboratories [K. S., S. C., D. W., F. A., P. C., I. M., C. P., G. K., M. F. L.] and Leukaemia Foundation of Queensland Research Laboratories [C. L., S-l. L.], The Queensland Institute of Medical Research, Herston, Brisbane, Queensland 4029, Australia; Hybridoma Unit, George S. Wise Faculty of Life Sciences [L. B-S.], and Department of Human Genetics, Sackler School of Medicine [N. I. S., Y. S.], Tel Aviv University, Ramat Aviv 69978, Israel; Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia [P. W.]; and Department of Surgery, University of Queensland, Herston, Brisbane, Queensland 4029, Australia [M. F. L.]

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-SRI, 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-SRI 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-SRI 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-SRI mice up to 40 weeks, after which time the animals died of other causes. The thymic lymphomas in Atm-SRI 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-SRI animals. Thus, expression of mutant protein in Atm-SRI 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.

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