Sci. Aging Knowl. Environ., 3 October 2001
Vol. 2001, Issue 1, p. tg1


atm-/- Strain 1;2001/1/tg1

Mouse atm-/- Strain 1
Genetic background 129/SvEv x NIH Black Swiss or 129/SvEv
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 5705 to 5882 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 Significantly reduced weight in comparison to wild-type littermates* during nursing, after weaning, and during the rapid growth period (heterozygotes are similar to the wild type); extremely poor growth of mutant embryonic fibroblasts (normal growth of heterozygous cells); extreme sensitivity to ionizing radiation leading to death through selective acute toxicity of the gastrointestinal tract rather than universal radiation toxicity; lack of gross ataxia*; no histological evidence of brain abnormality, yet demonstration of several neurological abnormalities by different tests of motor function; absence of oculocutaneous telangiectasia; extremely small gonads; total absence of mature gametes; reduction of mature single positive thymocytes (the cells deemed capable of activation based on their ability to express CD69); lack of abnormality in B cells in the periphery; development of thymic lymphoblastic lymphomas (monomorphic lymphoblastic cells with numerous mitotic figures) between 2 to 4 months of age with none of the afflicted mice surviving beyond 4.5 months.
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 C. Barlow, H. Hirotsune, R. Paylor, M. Liyanage, M. Eckhaus, F. Collins, Y. Shiloh, J. N. Crawley, T. Ried, D. Tagle, A. Wynshaw-Boris, Atm-deficient Mice: A paradigm of ataxia-telangiectasia. Cell 86, 159-171 (1996).
Additional references See below.
Source Authors of primary reference.
Other comments *Growth retardation is more pronounced in atm-deficient mice than in humans with AT. The opposite is true with respect to the neurological deficit.
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 2:;2001/1/tg2
atm-/- Strain 3:;2001/1/tg3
SAGE KE's Genes/Interventions database:;207
Keywords Ataxia telangiectasia, atm, phosphatidylinositol 3-kinase, lymphocytes, malignancy, p53
Prepared by Amir A. Sadighi Akha

October 3, 2001

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