Sci. Aging Knowl. Environ., 3 October 2001
Vol. 2001, Issue 1, p. tg2

GENETICALLY ALTERED MICE

atm-/- Strain 2

http://sageke.sciencemag.org/cgi/content/full/sageke;2001/1/tg2


Mouse atm-/- Strain 2
Genetic background C57BL/6 blastocysts implanted into BALB/c uteri
Gene changed atm (Different authors cite the mouse atm gene as ATM, Atm, or atm.)
Type of change Truncation mutation (disruption of the sequence corresponding to nucleotides 8619 to 8831 of the human atm gene)
Nature of protein The atm gene encodes a 370-kD member of the phosphatidylinositol 3-kinase (PI3-K)-related kinases (PIKK) family. It has a C-terminal sequence with significant homology to the catalytic domain of PI3-K and an adjacent domain related to the checkpoint gene rad-3. The atm protein has intrinsic protein kinase activity. No measurable lipid kinase function has yet been shown. Substrates for the atm protein include p53, p95/NBS1, MDM2, and CHK2.
Phenotype Slightly smaller size than wild-type littermates at 3 weeks of age; clear growth defect by 5 weeks of age that persists into adulthood (no growth defect in the heterozygotes); significantly increased sensitivity of ES cells to ionizing radiation; inefficient G1-S progression of murine embryonic fibroblasts and their essential senescence after passage 6*; defective reduction of the S-phase fraction in mouse embryonic fibroblasts following irradiation* that correlates with a defective up-regulation of p53; increased constitutive levels of p21 in mouse embryonic fibroblasts#; arrest of gametocyte development at the zygotene/pachytene stage of prophase I due to abnormal chromosomal synapsis; lack of cerebellar degeneration at the level of light microscopy; absence of any obvious abnormal behavior; reduction in the absolute number of both CD4+ CD8+ single-positive thymocytes with a particular reduction in the relative number of CD4+ cells; higher resistance of CD4+ CD8+ thymocytes from atm-/- mice to ionizing radiation-induced apoptosis; development of thymic lymphomas of CD4+ CD8+ origin; decreased number of B220+ IgM- pre-B cells in the bone marrow; a decrease in IgG2a, IgG2b, and IgG3 serum levels.
Corresponding human phenotype Ataxia telangiectasia (AT) is an autosomal recessive disorder presenting in childhood and characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia and variable immunodeficiency involving the function of both B and T lymphocytes. Chromosomal instability, increased sensitivity to ionizing radiation, a high incidence of hematolymphoid malignancies, growth retardation, incomplete sexual maturation, endocrine deficits, and premature aging of the skin and hair are other salient features of the disease.
Primary reference Y. Xu, D. Baltimore, Dual roles of ATM in the cellular response to radiation and in cell growth control. Genes Dev. 10, 2401-2410 (1996).
Y. Xu, T. Ashley, E. E. Brainerd, R. T. Bronson, M. S. Meyn, D. Baltimore, Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev. 10, 2411-2422 (1996).
Additional references See below.
Source Authors of primary references.
Other comments *The proliferation of fibroblasts from atm+/- is similar to the wild-type, but their response to irradiation is intermediate between their wild-type and knockout counterparts.
# This has not been detected in cells from individuals with AT.
While the 3 different atm knockout mice display very similar phenotypes, the following discrepancies exist:
1. Low animal weight is not perceived at the same time in the 3 distinct knockouts.
2. B cell numbers are deemed normal in some groups, but not others (which in itself is consistent with the phenotypes of humans with the disease).
Other links Related transgenic/knockout mice:
atm-/- Strain 1: http://sageke.sciencemag.org/cgi/content/full/sageke;2001/1/tg1
atm-/- Strain 3: http://sageke.sciencemag.org/cgi/content/full/sageke;2001/1/tg3
SAGE KE's Genes/Interventions database: http://sageke.sciencemag.org/cgi/genedata/sagekeGdbGene;207
Keywords Ataxia telangiectasia, atm, phosphatidylinositol 3-kinase, lymphocytes, malignancy, p53
Prepared by Amir A. Sadighi Akha

October 3, 2001

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