Phenotypic cellular characterization of an ataxia telangiectasia patient carrying a causal homozygous missense mutation.

Most disease-causing mutations in Ataxia telangiectasia (AT) patients correspond to truncating mutations in the ATM gene with very few cases of AT patients carrying two missense sequence alterations being reported. The cellular phenotype of a lymphoblastoid cell line established from an AT patient (AT173) who showed classical clinical AT features, and carried two homozygous missense alterations, the 378T>A variant and 9022C>T located within the ATM kinase domain, has been characterized. ATM mRNA was detectable and the ATM protein level was approximately 50% of that seen in normal cell lines. Functional analysis of this protein revealed a total absence of ATM kinase activity measured either in vitro or in vivo, before and after exposure to ionizing radiation. The AT173 cell line was hypersensitive to ionizing radiation and exhibited a G1 cell cycle arrest defect and an accumulation of cells in G2 phase of the cell cycle after irradiation, a response that is identical to that seen in AT cell lines carrying truncating mutations. These phenotypic features strongly suggest that the 9022C>T (R3008C) missense mutation is the disease-causing mutation and that the presence of ATM protein is not always predictive of a normal cellular phenotype.