Atm knock-in mice harboring an in-frame deletion corresponding to the human ATM 7636de19 common mutation exhibit a variant phenotype

Kevin Spring, Simone Cross, Chung Li, Dianne Watters, Liat Ben-Senior, Paul Waring, Farida Ahangari, Shan Ii Lu, Philip Chen, Ihor Misko, Carol Paterson, Graham Kay, Nechama I. Smorodinsky, Yosef Shiloh, Martin F. Lavin

Research output: Contribution to journalArticlepeer-review

Abstract

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-ΔSRI, was designed as a model of one of the most common deletion mutations (7636de19) 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-ΔSRI 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-ΔSRI 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-ΔSRI mice up to 40 weeks, after which time the animals died of other causes. The thymic lymphomas in Atm-ΔSRI 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-ΔSRI animals. Thus, expression of mutant protein in Atm-ΔSRI 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.

Original languageEnglish
Pages (from-to)4561-4568
Number of pages8
JournalCancer Research
Volume61
Issue number11
StatePublished - 1 Jun 2001

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