We modeled ATM sequence variants identified in UK A-T patients to determine the stability and kinase activity of the resulting proteins as well as the distribution of these mutations across the coding region.
These data suggest that although ATM-specific mRNA is abundant in A-T cells, the abnormal ATM protein is unstable and is quickly targeted for degradation.
We quantified ATM protein expression in four of the families and found variable ATM protein expression (0-6.4%), further evidence for mutant ATM protein expression in both classic and variant A-T patients.
Ataxia-telangiectasia in the Japanese population: identification of R1917X, W2491R, R2909G, IVS33+2T-->A, and 7883del5, the latter two being relatively common mutations.
In our study, we have determined the ATM mutation spectrum in 19 classical A-T patients, including some immigrant populations, as well as 12 of Dutch ethnic origin.
We also show that 25% of all A-T patients carried in-frame deletions or missense mutations, many of which were also associated with expression of mutant ATM protein.
We also provide evidence that ATM protein binds to p53 and this association is defective in A-T cells compatible with the defective p53 response in these cells.
We have identified 14 families with ataxia-telangiectasia (A-T) in which mutation of the ATM gene is associated with a less severe clinical and cellular phenotype (approximately 10%-15% of A-T families identified in the United Kingdom).
The development of DNA-based methods for detection of unknown mutations and further characterization of ATM mutation pattern will facilitate identification of A-T carriers and assessment of their cancer risk.