Characterization of ATM gene mutations in 66 ataxia telangiectasia families

Abstract

Ataxia telangiectasia (AT) is an autosomal recessive disease characterized by neurological and immunological symptoms, radiosensitivity and cancer predisposition. The gene mutated in AT, designated the ATM gene, encodes a large protein kinase with a PI-3 kinase-related domain. In this study, we investigated 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 flanking untranslated regions from genomic DNA of 66 unrelated AT patients. We identified 46 different ATM mutations and 26 sequence polymorphisms and variants scattered throughout the gene. A total of 34 mutations have not been described in other populations. Seven mutations occurred in more than one family, but none of these accounted for more than five alleles in our patient group. The majority of the mutations were truncating, confirming that the absence 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 for two mutations. Immunoblot studies of cell lines carrying ATM missense substitutions or in-frame deletions detected residual ATM protein in four cases. 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 variations 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.

ATM polymorphisms as risk factors for prostate cancer development

“…The frequencies of the variant alleles 5557A, 5558T and 3161G are in good agreement with previous studies in the Caucasian population (Dork et al, 2001;Spurdle et al, 2002;Mauget-Faysse et al, 2003). The frequency of the intronic SNPs ivs38-15g4c (Thorstenson et al, 2001) and ivs38-8t4c (Sandoval et al, 1999) have previously only been determined in a small number of individuals. The ivs38-15 is the rarer of the two variants, the c allele being present at an allele frequency of 0.004, while the ivs38-8c allele is found at a frequency of 0.036.…”

“…Strong linkage disequilibrium has been found between 3161G (P1054R) and the variant allele at 2572C (F858L). It has also been found to occur in cis to the splicing mutation 3576G to A found in some AT patients of South or South East European descent (Sandoval et al, 1999) although this splicing mutation was neither present in the patient HA220 nor in any other breast cancer patient carrying the 3161G allele (Dork et al, 2001). There may, however, be other variants on this haplotype (including noncoding alterations) that have not been studied.…”

Underexpression and abnormal localization of ATM products in ataxia telangiectasia patients bearing ATM missense mutations

“…In agreement with previous studies, 19,[28][29][30][31][32] we showed a decreased ATM protein in 14 of the 16 A-T confirmed cell lines. Recent studies based on transfection of ATM constructs carrying various missense mutations showed that some missense mutations were associated with decreased ATM protein expression.…”

ATM germline heterozygosity does not play a role in chronic lymphocytic leukemia initiation but influences rapid disease progression through loss of the remaining ATM allele

“…16 The PCR products were sequenced whenever variant chromatogram patterns were detected. 3,4 Sequence changes were compared to published results 17,18 and ATM databases (http://chromium.liacs.nl/LOVD2/home.php). To exclude consideration of rare polymorphisms, sequence changes were classified as pathogenic mutations only if they were previously reported as causative mutations in AT patients or were predicted to cause protein truncation.…”