PREDOMINANCE OF NULL MUTATIONS IN ATAXIA-TELANGIECTASIA

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involvi ng cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition. The responsible gene, AIM , was recently identified by positional cloning and found to encode a putative 350 kDa protein with a PI 3-kinase-like domain, presumably in volved in mediating cell cycle arrest in response to radiation-induced DNA damage. The nature and location of A-T mutations should provide i nsight into the function of the ATM protein and the molecular basis of this pleiotropic disease. Of 44 A-T mutations identified by us to dat e, 39 (89%) are expected to inactivate the ATM protein by truncating i t, by abolishing correct initiation or termination of translation, or by deleting large segments. Additional mutations are four smaller in-f rame deletions and insertions, and one substitution of a highly conser ved amino acid at the PI 3-kinase domain. The emerging profile of muta tions causing A-T is thus dominated by those expected to completely in activate the AIM protein. ATM mutations with milder effects may result in phenotypes related, but not identical, to A-T.