Residual ataxia telangiectasia mutated protein function in cells from ataxia telangiectasia patients, with 5762ins137 and 7271T -> G mutations, showing a less severe phenotype

We have assessed several ataxia Telangiectasia mutated (ATM)-dependent func tions in cells derived from ataxia telangiectasia patients, carrying either an ATM 5762ins137 splice site or a 7271T -->G missense mutation, with a le ss severe phenotype compared with the classical disorder. ATM kinase in vit ro, from 5762ins137 cells, showed the same specific activity as ATM in norm al cells, but the protein was present at low levels. In contrast, mutant AT M kinase activity in the 7271T -->G cells was only about 6% that of the act ivity in normal cells, although the level of mutant protein expressed was s imilar to normal cells. Phosphorylation of the DNA double strand break repa ir proteins Nbs1 and hMre11, following DNA damage, was observed in normal a nd 7271T -->G cells but was almost absent in both 5762ins137 and classical ataxia telangiectasia cells. The kinetics of p53 response was intermediate between normal and classical ataxia telangiectasia cells in both the 7271T -->G and 5762ins137 cells, but interestingly, c-Jun kinase activation follo wing DNA damage was equally deficient in cell lines derived from all the at axia telangiectasia patients. Our results indicate that levels of ATM kinas e activity, but not induction of p53 or e-Jun kinase activity, in these cel ls correlate with the degree of neurological disorder in the patients.