Characterization of ATM gene mutations in 66 ataxia telangiectasia families

Ataxia telangiectasia (AT) is an autosomal recessive disease characterized by neurological and immunological symptoms, radiosensitivity and cancer pre disposition. The gene mutated in AT, designated the ATM gene, encodes a lar ge protein kinase with a PI-3 kinase-related domain. In this study, we inve stigated the mutational spectrum of the ATM gene in a cohort of AT patients living in Germany. We amplified and sequenced all 66 exons and the flankin g untranslated regions from genomic DNA of 66 unrelated AT patients. We ide ntified 46 different ATM mutations and 26 sequence polymorphisms and varian ts scattered throughout the gene. A total of 34 mutations have not been des cribed in other populations. Seven mutations occurred in more than one fami ly, but none of these accounted for more than five alleles in our patient g roup. The majority of the mutations were truncating, confirming that the ab sence of full-length ATM protein is the most common molecular basis of AT, Transcript analyses demonstrated single exon skipping as the consequence of most splice site substitutions, but a more complex pattern was observed fo r two mutations. Immunoblot studies of cell lines carrying ATM missense sub stitutions or in-frame deletions detected residual ATM protein in four case s. One of these mutations, a valine deletion proximal to the kinase domain, resulted in ATM protein levels >20% of normal in an AT lymphoblastoid cell line. In summary, our results survey and characterize a plethora of variat ions in the ATM gene identified by exon scanning sequencing and indicate a high diversity of mutations giving rise to AT in a non-isolated population.