The ATM gene is responsible for the autosomal recessive disorder AtaxiaTelangiectasia (AT). Many different mutations, located all across the gene, have been reported with a predominance of truncating mutations. By using PTT (protein truncation test) a mutation was found in one Norwegian AT family. Sequencing revealed that the mutation affected nucleotides 3245-3247, codon 1082, and changed the sequence from ATC to TGAT, inducing a stop codon downstream at codon 1095 and leading to early truncation of the ATM protein. Perpendicular DGGE (denaturing gradient gel electrophoresis) was used to screen 10 additional families for this mutation. The 3245 delATC insTGAT mutation was found in 12 of 22 proband alleles: five patients were homozygotes and two heterozygotes. Haplotype analyses were performed using eight microsatellite markers, within and flanking the ATM gene. All carriers of the mutation described were found to have a common haplotype of the five closest CA-repeat microsatellite markers. Genealogical investigations of the families identified a common ancestor for three of the families. The common ancestor was a woman born in 1684 in the area from which these families originate. The prevalence of this mutation in Norwegian patients now allows a major subset of AT heterozygotes to be identified, both in the general population and in breast cancer patients, so that their cancer risk can be evaluated
The Ataxia Telangiectasia Mutation (ATM) gene is mutated in the rare recessive syndrome Ataxia Telangiectasia (AT), which is characterized by cerebellar degeneration, immunodeficiency, and cancer predisposition. In this study, 41 AT families from Denmark, Finland, Norway, and Sweden were screened for ATM mutations. The protein truncation test (PTT), fragment length and heteroduplex analyses of large (0.8–1.2 kb) cDNA fragments were used. In total, 67 of 82 (82%) of the disease‐causing alleles were characterized. Thirty‐seven unique mutations were detected of which 25 have not previously been reported. The mutations had five different consequences for the ATM transcript: mutations affecting splicing (43%); frameshift mutations (32%); nonsense mutations (16%); small in‐frame deletions (5%); and one double substitution (3%). In 28 of the probands mutations were found in both alleles, in 11 of the probands only one mutated allele was detected, and no mutations were detected in two Finnish probands. One‐third of the probands (13) were homozygous, whereas the majority of the probands (26) were compound heterozygote with at least one identified allele. Ten alleles were found more than once; one Norwegian founder mutation constituted 57% of the Norwegian alleles. Several sequence variants were identified, none of them likely to be disease‐causing. Some of them even involved partial skipping of exons, leading to subsequent truncation of the ATM protein. Hum Mutat 16:232–246, 2000. © 2000 Wiley‐Liss, Inc.
Previous reports have suggested that heterozygotes for ataxia-telangiectasia (A-T) have an increased risk of cancer, in particular breast cancer. The ATM gene, responsible for A-T, was recently cloned. Loss of heterozygosity (LOH) in the chromosome band 11q23, where the ATM gene is located, has been reported in several types of tumours including breast carcinomas. Whether the ATM gene is the target, and the sole target, for the LOH seen in this region is not yet known. In this study, 169 primary breast carcinomas and 10 metastases were examined for allelic imbalance (AI) using 10 microsatellite markers mapping to 11q23.1. Nine of the markers reside within a 10 Mb region surrounding the ATM gene, whereas the tenth locus, APOC-3, is located more than 12 Mb telomeric from this region. The highest frequencies of alteration were found for APOC-3 (45%), and for two markers located approximately 200 and 900 kb telomeric from ATM, D11S1294 (44%) and D11S1818 (44%). The marker located within the ATM gene, D11S2179, was altered in 37% of the informative tumours. The present deletion map indicates that three distinct regions at 11q23.1 may be involved in breast cancer development; one between the markers D11S1294 and D11S1818, a second close to APOC-3, and a third that is possibly the ATM-gene itself.
This work describes the isolation and characterization of methyl methanesulfonate (MMS) and ethyl methanesulfonate (EMS) induced 6-thioguanine-resistant mutants in normal and Escherichia coli tag gene expressing Chinese hamster fibroblast, RJKO, cells. It was previously shown that increased removal of 3-alkylated adenine, effected by 3-methyladenine DNA glycosylase I (Tag), reduces the frequencies of hprt mutations induced by alkylating agents which produce mostly N-alkylation (MMS and EMS) to half the normal rate. In order to identify which type of mutation is suppressed by increased 3-alkyladenine repair we have determined the DNA base sequence changes of the hprt cDNA in 61 independent MMS- and EMS-induced mutant clones. For both cell types and irrespective of the agent used, the majority of mutations were GC to AT transitions originating in the non-transcribed strand. Only 6/55 base substitutions occurred at AT base pairs: five AT to GC transitions and one AT to CG transversion. Six mutations were found to be deletions. These results indicate that 3-alkylated adenines in DNA are not directly premutagenic. The fact that the mutation frequency is reduced by increased 3-alkyladenine removal might be explained by postulating the existence in mammalian cells of an SOS-like response turned on by cytotoxic lesions like 3-alkyladenine, or, alternatively, that increased removal of 3-alkyladenine increases the number of single-strand breaks in DNA, which stalls DNA replication and allows a prolonged time for DNA repair by the alkyltransferase.
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