title: Atm knock-in mice harboring an in-frame deletion corresponding to the human ATM 7636del9 common mutation exhibit a variant phenotype.
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-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.
authors.affiliation: Queensland Cancer Fund Research Laboratories, The Queensland Institute of Medical Research, P.O. Box Royal Brisbane Hospital, Herston, Brisbane, Queensland 4029, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Spring
authors.forename: S
authors.initials: S
authors.lastname: Cross
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.forename: D
authors.initials: D
authors.lastname: Watters
authors.forename: L
authors.initials: L
authors.lastname: Ben-Senior
authors.forename: P
authors.initials: P
authors.lastname: Waring
authors.forename: F
authors.initials: F
authors.lastname: Ahangari
authors.forename: S L
authors.initials: SL
authors.lastname: Lu
authors.forename: P
authors.initials: P
authors.lastname: Chen
authors.forename: I
authors.initials: I
authors.lastname: Misko
authors.forename: C
authors.initials: C
authors.lastname: Paterson
authors.forename: G
authors.initials: G
authors.lastname: Kay
authors.forename: N I
authors.initials: NI
authors.lastname: Smorodinsky
authors.forename: Y
authors.initials: Y
authors.lastname: Shiloh
authors.forename: M F
authors.initials: MF
authors.lastname: Lavin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001260:Ataxia Telangiectasia / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D018797:Cell Cycle Proteins; D003433:Crosses, Genetic; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains / Q000235:genetics* / Q000254:growth & development / Q000276:immunology; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D017384:Sequence Deletion; D013953:Thymus Neoplasms / Q000235:genetics; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D004247:DNA; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases