The ATM gene and mutations

The AT gene was isolated in 1995, culminating a 14-year positional cloning effort by an international consortium of investigators. The ATM gene and gene products are very large: 3056 amino acids, 350 kDa protein, and a 13 kb transcript that may be alternatively spliced in some tissues. The ATM gene is expressed in all tissues tested. The gene has 66 exons, each of about 100-300 base pairs in length; these are spread over about 150 kb of genomic DNA at chromosome llq23.1. Eighty-five per cent of mutations result in a shortened (truncated) protein. Since the gene has a phosphotidylinositol 3-kinase domain at the 3' end, truncated proteins probably will be lacking this important functional domain. Many of these truncations result from deletions of 1, 2 and 3 exons because of mutations at splice sites. About 200 mutations have been characterized thus far (Figure 3); only two potential hotspots can be appreciated at exons 54 and 16. The rest of the mutations are found across the entire gene, making it difficult to identify each patient's mutations without a great deal of screening of the gene. The most useful screening techniques thus far have been protein truncation testing (PTT), single-strand conformational analysis (SSCA), heteroduplex analysis (HA), conformation-sensitive gel electrophoresis (CSGE), RNAase cleavage assay (RCA), and restriction endonuclease fingerprinting (REF). Each of these must then be followed by DNA sequencing to identify the actual site of the mutation. A few common mutations have been identified and can be tested easily among Amish, Central-Southern Italians, Moroccan Jews, Midland English, Norwegians, Costa Ricans and Polish.

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