A gene, ATM, that is mutated in the autosomal recessive disorder ataxia telangiectasia (AT) was identified by positional cloning on chromosome 11q22-23. AT is characterized by cerebellar degeneration, immunodeficiency, chromosomal instability, cancer predisposition, radiation sensitivity, and cell cycle abnormalities. The disease is genetically heterogeneous, with four complementation groups that have been suspected to represent different genes. ATM, which has a transcript of 12 kilobases, was found to be mutated in AT patients from all complementation groups, indicating that it is probably the sole gene responsible for this disorder. A partial ATM complementary DNA clone of 5.9 kilobases encoded a putative protein that is similar to several yeast and mammalian phosphatidylinositol-3' kinases that are involved in mitogenic signal transduction, meiotic recombination, and cell cycle control. The discovery of ATM should enhance understanding of AT and related syndromes and may allow the identification of AT heterozygotes, who are at increased risk of cancer.

https://science.sciencemag.org/content/sci/268/5218/1749.full.pdf

A single ataxia telangiectasia gene with a product similar to pi-3 kinase

Polygenic disease: methods for mapping complex disease traits

Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions

The ataxia-telangiectasia mutated (ATM) gene, which is mutated in the autosomal recessive disorder ataxia-telangiectasia (AT), was isolated in 1995 by positional cloning. Although in vitro cell fusion studies had suggested that AT was genetically heterogeneous, all AT patients studied to date have been found to harbor mutations in the ATM gene. More that 100 ATM mutations occurring in AT patients have been documented. The mutations are broadly distributed throughout the ATM gene. Except for patients from families with known consanguinity, most AT patients are compound heterozygotes. The majority (> 70%) of mutations are predicted to lead to protein truncation. A significant number of the reported mutations affect mRNA splicing with at least half of the coding exons (32/62) having been observed to undergo exon skipping. The large size of the ATM gene, 66 exons spanning approximately 150 kb of genomic DNA, together with the diversity and broad distribution of mutations in AT patients greatly limits the utility of direct mutation screening as a diagnostic tool, or method of carrier identification, except where founder effect mutations are involved.

Diversity of ATM gene mutations detected in patients with ataxia‐telangiectasia

To facilitate the evaluation of ATM heterozygotes for susceptibility to other diseases, such as breast cancer, we have attempted to define the most common mutations and their frequencies in ataxia-telangiectasia (A-T) homozygotes from 10 ethnic populations. Both genomic mutations and their effects on cDNA were characterized. Protein-truncation testing of the entire ATM cDNA detected 92 (66%) truncating mutations in 140 mutant alleles screened. The haplotyping of patients with identical mutations indicates that almost all of these represent common ancestry and that very few spontaneously recurring ATM mutations exist. Assays requiring minimal amounts of genomic DNA were designed to allow rapid screening for common ethnic mutations. These rapid assays detected mutations in 76% of Costa Rican patients (3), 50% of Norwegian patients (1), 25% of Polish patients (4), and 14% of Italian patients (1), as well as in patients of Amish/Mennonite and Irish English backgrounds. Additional mutations were observed in Japanese, Utah Mormon, and African American patients. These assays should facilitate screening for A-T heterozygotes in the populations studied.

Ataxia-Telangiectasia: Identification and Detection of Founder-Effect Mutations in the ATM Gene in Ethnic Populations

In an effort to localize a gene for ataxia-telangiectasia (A-T), we have genotyped 27 affected Costa Rican families, with 13 markers, in the chromosome 11q22-23 region. Significant linkage disequilibrium was detected for 9/13 markers between D11S1816 and D11S1391. Recombination events observed in these pedigrees places A-T between D11S1819 and D11S1960. One ancestral haplotype is common to 24/54 affected chromosomes and roughly two-thirds of the families. Inferred (ancestral) recombination events involving this common haplotype in earlier generations suggest that A-T is distal to D11S384 and proximal to D11S1960. Several other common haplotypes were identified, consistent with multiple mutations in a single gene. When considered together with all other evidence, this study further sublocalizes the major A-T locus to ≈200 kb, between markers S384 and S535.

Sublocalization of an ataxia-telangiectasia gene distal to D11S384 by ancestral haplotyping in Costa Rican families.

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Sublocalization of an ataxia-telangiectasia gene distal to D11S384 by ancestral haplotyping in Costa Rican families.