Ataxia-telangiectasia (AT) is a autosomal recessive disorder characterized by cerebellar degeneration and oculocuteneous telangiectasia, accompanied by severe immunodeficiency and increased cancer predisposition. The AT gene product appears to participate in cell cycle checkpoints, and cell lines from AT patients show profound sensitivity to the cytotoxic and clastogenic effects of ionizing radiation and radiomimetic chemicals. Heterozygous carriers appear to have an increased predisposition to cancer, particularly for breast cancer. To address the complex relationship between gene function and the pleiotropic AT phenotype, a murine model of ataxia-telangiectasia was created by disrupting the Atm locus via gene targeting. Mice homozygous for the disrupted Atm allele displayed growth retardation, neurologic dysfunction, male and female infertility secondary to the absence of mature gametes, defects in T lymphocyte maturation, and extreme sensitivity to g-irradiation. The majority of animals developed malignant thymic lymphomas between two and four months of age. Several chromosomal anomalies were detected in one of these tumors. Fibroblasts from these mice grew slowly, and exhibited abnormal radiation-induced G1 checkpoint function. Atm-disrupted mice recapitulate the A-T phenotype in humans, providing a mammalian model in which to study the pathophysiology of this pleiotropic disorder.
