TARGETED DISRUPTION OF ATM LEADS TO GROWTH-RETARDATION, CHROMOSOMAL FRAGMENTATION DURING MEIOSIS, IMMUNE DEFECTS, AND THYMIC LYMPHOMA

ATM, the gene mutated in the inherited human disease ataxia-telangiect asia, is a member of a family of kinases involved in DNA metabolism an d cell-cycle checkpoint control. To help clarify the physiological rol es of the ATM protein, we disrupted the ATM gene in mice through homol ogous recombination, Initial evaluation of the ATM knockout animals in dicates that inactivation of the mouse ATM gene recreates much of the phenotype of ataxia-telangiectasia. The homozygous mutant (ATM(-/-)) m ice are viable, growth-retarded, and infertile. The infertility of ATM (-/-) mice results from meiotic failure. Meiosis is arrested at the zy gotene/pachytene stage of prophase I as a result of abnormal chromosom al synapsis and subsequent chromosome fragmentation. Immune defects al so are evident in ATM(-/-) mice, including reduced numbers of B220(+)C D43(-) pre-B cells, thymocytes, and peripheral T cells, as well as fun ctional impairment of T-cell-dependent immune responses. The cerebella of ATM(-/-) mice appear normal by histologic examination at 3 to 4 mo nths and the mice have no gross behavioral abnormalities. The majority of mutant mice rapidly develop thymic lymphomas and die before 4 mont hs of age. These findings indicate that the ATM gene product plays an essential role in a diverse group of cellular processes, including mei osis, the normal growth of somatic tissues, immune development, and tu mor suppression.