Predominance of null mutations in ataxia-telangiectasia

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involvingcerebellar degeneration, immunodeficiency, chromosomal instability,radiosensitivity and cancer predisposition. The responsible gene, ATM, wasrecently identified by positional cloning and found to encode a putative350 kDa protein with a Pl 3-kinase-like domain, presumably involved inmediating cell cycle arrest in response to radiation-induced DNA damage.The nature and location of A-T mutations should provide insight into thefunction of the ATM protein and the molecular basis of this pleiotropicdisease. Of 44 A-T mutations identified by us to date, 39 (89%) areexpected to inactivate the ATM protein by truncating it, by abolishingcorrect initiation or termination of translation, or by deleting largesegments. Additional mutations are four smaller in-frame deletions andinsertions, and one substitution of a highly conserved amino acid at the Pl3-kinase domain. The emerging profile of mutations causing A-T is thusdominated by those expected to completely inactivate the ATM protein. ATMmutations with milder effects may result in phenotypes related, but notidentical, to A-T.