Atm knock-in mice harboring an in-frame deletion corresponding to the human ATM 7636del9 common mutation exhibit a variant phenotype

Spring, K., Cross, S., Li, C., Watters, D., Ben-Senior, L., Waring, P., Ahangari, F., Lu, S. L., Chen, P., Misko, I., Paterson, C., Kay, G., Smorodinsky, N. I., Shiloh, Y. and Lavin, M. F. (2001) Atm knock-in mice harboring an in-frame deletion corresponding to the human ATM 7636del9 common mutation exhibit a variant phenotype. Cancer Research, 61 11: 4561-4568.


Author Spring, K.
Cross, S.
Li, C.
Watters, D.
Ben-Senior, L.
Waring, P.
Ahangari, F.
Lu, S. L.
Chen, P.
Misko, I.
Paterson, C.
Kay, G.
Smorodinsky, N. I.
Shiloh, Y.
Lavin, M. F.
Title Atm knock-in mice harboring an in-frame deletion corresponding to the human ATM 7636del9 common mutation exhibit a variant phenotype
Journal name Cancer Research   Check publisher's open access policy
ISSN 0008-5472
Publication date 2001-01-01
Sub-type Article (original research)
Open Access Status Not Open Access
Volume 61
Issue 11
Start page 4561
End page 4568
Total pages 8
Place of publication Birmingham. USA
Publisher American Association for Cancer Research
Language eng
Subject C1
321015 Oncology and Carcinogenesis
730108 Cancer and related disorders
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, Abm-Delta SRI, 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-Delta 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-Delta 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-Delta SRI mice up to 40 weeks, after which time the animals died of other causes. The thymic lymphomas in Atm-Delta 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-Delta SRI animals. Thus, expression of mutant protein in Atm-Delta 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.
Keyword Oncology
Ataxia-telangiectasia
Deficient Mice
Ionizing-radiation
V(d)j Recombination
Human-lymphocytes
Thymic Lymphoma
Up-regulation
Cell-death
Dna-damage
Fas Ligand
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 48 times in Thomson Reuters Web of Science Article | Citations
Google Scholar Search Google Scholar
Created: Wed, 15 Aug 2007, 01:30:55 EST