title: A novel mouse model for ataxia-telangiectasia with a N-terminal mutation displays a behavioral defect and a low incidence of lymphoma but no increased oxidative burden.
abstract: Ataxia-telangiectasia (A-T) is a rare multi-system disorder caused by mutations in the ATM gene. Significant heterogeneity exists in the underlying genetic mutations and clinical phenotypes. A number of mouse models have been generated that harbor mutations in the distal region of the gene, and a recent study suggests the presence of residual ATM protein in the brain of one such model. These mice recapitulate many of the characteristics of A-T seen in humans, with the notable exception of neurodegeneration. In order to study how an N-terminal mutation affects the disease phenotype, we generated an inducible Atm mutant mouse model (Atm(tm1Mmpl/tm1Mmpl), referred to as A-T [M]) predicted to express only the first 62 amino acids of Atm. Cells derived from A-T [M] mutant mice exhibited reduced cellular proliferation and an altered DNA damage response, but surprisingly, showed no evidence of an oxidative imbalance. Examination of the A-T [M] animals revealed an altered immunophenotype consistent with A-T. In contrast to mice harboring C-terminal Atm mutations that disproportionately develop thymic lymphomas, A-T [M] mice developed lymphoma at a similar rate as human A-T patients. Morphological analyses of A-T [M] cerebella revealed no substantial cellular defects, similar to other models of A-T, although mice display behavioral defects consistent with cerebellar dysfunction. Overall, these results suggest that loss of Atm is not necessarily associated with an oxidized phenotype as has been previously proposed and that loss of ATM protein is not sufficient to induce cerebellar degeneration in mice.
authors: Department of Biomedical Genetics, University of Rochester, 601 Elmwood Avenue, Box 633, Rochester, NY 14642, USA, Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, NY 14642, USA and.
authors: Andrew
authors: A
authors: Campbell
authors: Department of Biomedical Genetics, University of Rochester, 601 Elmwood Avenue, Box 633, Rochester, NY 14642, USA.
authors: Brittany
authors: B
authors: Krupp
authors: Division of Pharmaceutical Sciences, University of Wyoming School of Pharmacy, 1000 East University Ave., Dept. 3375, Laramie, WY 82071, USA.
authors: Jared
authors: J
authors: Bushman
authors: Department of Biomedical Genetics, University of Rochester, 601 Elmwood Avenue, Box 633, Rochester, NY 14642, USA.
authors: Mark
authors: M
authors: Noble
authors: Department of Biomedical Genetics, University of Rochester, 601 Elmwood Avenue, Box 633, Rochester, NY 14642, USA.
authors: Christoph
authors: C
authors: Pröschel
authors: Department of Biomedical Genetics, University of Rochester, 601 Elmwood Avenue, Box 633, Rochester, NY 14642, USA, margot_mayer-proschel@urmc.rochester.edu.
authors: Margot
authors: M
authors: Mayer-Pröschel
mesh_terms: D000818:Animals; D001260:Ataxia Telangiectasia / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D015994:Incidence; D016399:Lymphoma, T-Cell / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010084:Oxidation-Reduction; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse