Ataxia telangiectasia — caused by homozygous mutations in ATM — has long been linked with radiosensitivity, genomic instability and a predisposition to cancer, but do heterozygous individuals also share these characteristics? Martin Lavin and colleagues, reporting in the September issue of Nature Genetics, have used a mouse model to investigate this question, and have moved one step closer to the answer.

An ATM missense mutation — 7636del9, which results in the in-frame deletion of three amino acids — has been identified in individuals with ataxia telangiectasia. The corresponding homozygous mutation in mice ( Atm -ΔSRI) also increases tumour incidence. So what about mice that are heterozygous for Atm-ΔSRI? These also showed an increase in tumour formation — 8.9% compared with 2.8% in wild-type littermates — and the tumour spectrum was similar, but not identical, to that found in mice that were homozygous for this mutation. Humans who were heterozygous for this mutation were analysed for tumour incidence, and were shown to exhibit a small increase; however, this was not statistically significant. Might these individuals, instead, display some of the other features of ataxia telangiectasia?

Heterozygous human and mouse cells were isolated, and were examined for survival and genomic instability following exposure to radiation. The level of radiation-induced death and the number of chromosome aberrations were found to be intermediate between wild-type and homozygous-mutant cells.

The ATM protein kinase protects cells from DNA damage by phosphorylating and activating proteins such as p53. So is this ability impaired in ATM-ΔSRI mutants? Wild-type or ΔSRI-ATM DNA was transfected into control lymphoblastoid cells, and kinase assays were performed on immunoprecipitated ATM, using p53 as a substrate. Kinase activity was abolished in cells that were transfected with the ΔSRI mutant, indicating that it acts as a dominant-negative inhibitor of the wild-type protein. This lends support to the finding that mice that are heterozygous for an Atm deletion do not have an increased tumour incidence, and indicates that cancer predisposition in heterozygous carriers of ATM mutants could crucially depend on the specific mutation involved.

Hopefully, the cancer risk of other carriers of ATM mutations will soon be accurately determined, so that individuals are able to take any recommended precautions.