New mutations in the ATM gene and clinical data of 25 AT patients.

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar degeneration, immunodeficiency, oculocutaneous telangiectasias, chromosomal instability, radiosensitivity, and cancer predisposition. The gene mutated in the patients, ATM, encodes a member of the phosphatidylinositol 3-kinase family proteins. The ATM protein has a key role in the cellular response to DNA damage. Truncating and splice site mutations in ATM have been found in most patients with the classical AT phenotype. Here we report of our extensive ATM mutation screening on 25 AT patients from 19 families of different ethnic origin. Previously unknown mutations were identified in six patients including a new homozygous missense mutation, c.8110T>C (p.Cys2704Arg), in a severely affected patient. Comprehensive clinical data are presented for all patients described here along with data on ATM function generated by analysis of cell lines established from a subset of the patients.

IVS10-6T>G, an ancient ATM germline mutation linked with breast cancer.

Patients with autosomal recessive multisystemic disorder ataxia-telangiectasia are homozygous or compound heterozygous for mutations in the ataxia-telangiectasia mutated (ATM) gene. Heterozygous carriers of an ATM germline mutation have an increased susceptibility for breast cancer. The subject of this study is one particular germline mutation, the ATM exon 11 splice-site mutation IVS10-6T>G, that has been identified as being associated with an increased risk for breast cancer both in the general population and in high-risk breast cancer families. We investigated the natural history of this mutation, i.e., whether it is frequently arising de novo in a population, or whether it can be traced back to a single ancient mutational event. Genotyping of a number of polymorphic markers (two extragenic and two intragenic microsatellite loci, a single nucleotide insertion/deletion polymorphism, and a dinucleotide insertion/deletion polymorphism) was performed in 18 samples from different populations carrying the IVS10-6T>G mutation (17 unrelated breast cancer patients who were heterozygous carriers of this mutation and a single A-T patient who was homozygous for the IVS10-6T>G mutation). The same markers were also genotyped among 39 unrelated healthy individuals without this mutation. Haplotype analyses revealed one common ancestor in all mutation carriers. By means of a maximum likelihood method, we estimated the age of this mutation to be approximately 2,000 generations. We provide evidence that the IVS10-6T>G mutation occurred only once during human evolution, at least 50,000 years ago. Our results predict that this mutation could be widely distributed across Europe and, probably, the Middle East and Western Asia.