Ataxia-telangiectasia (A-T) is a autosomal recessive disorder characterized by cerebellar degeneration and oculocuteneous telangiectasia, accompanied by severe immunodeficiency and increased cancer predisposition. Cell lines from A-T patients show profound sensitivity to ionizing radiation and radiomimetic chemicals. Heterozygous carriers appear to have an increased predisposition to cancer, particularly for breast cancer. The gene responsible for A-T has been isolated, and has homology to rad3 and phosphoinositol-3-kinase, supporting its involvement in cell cycle regulation. We have isolated mouse genomic clones and constructed a targeting vector to create a null allele for the murine A-T gene. The targeting vector was transfected into embryonic stem cells, and cells containing the targeted disruption have been isolated. The targeted clones have an increased sensitivity to radiomimetic drugs, indicating that the mutation introduced in the mouse homolog behaves in a predicable fashion. These cells have been injected into blastocysts to generate chimeric mice and to establish this disrupted allele in the mouse germline.
