A Single Ataxia Telangiectasia Gene with a Product Similar to PI-3 Kinase

TLDR

AT is an autosomal recessive disorder marked by cerebellar degeneration, immunodeficiency, chromosomal instability, cancer predisposition, radiation sensitivity, and cell‑cycle abnormalities, and its genetic heterogeneity has suggested up to four distinct genes. Identifying ATM aims to deepen understanding of AT and related syndromes and to enable detection of heterozygous carriers at elevated cancer risk. A 5.9‑kb partial ATM cDNA encodes a protein homologous to yeast and mammalian phosphatidylinositol‑3′ kinases involved in mitogenic signaling, meiotic recombination, and cell‑cycle control. Positional cloning on chromosome 11q22‑23 revealed that a 12‑kb ATM gene is mutated in all AT complementation groups, indicating it is the sole gene responsible for the disorder.

Abstract

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.