GENOTYPE-PHENOTYPE RELATIONSHIPS IN ATAXIA-TELANGIECTASIA AND VARIANTS

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder charact erized by cerebellar degeneration, immunodeficiency, chromosomal insta bility, radiosensitivity, and cancer predisposition. A-T cells are sen sitive to ionizing radiation and radiomimetic chemicals and fail to ac tivate cell-cycle checkpoints after treatment with these agents. The r esponsible gene, ATM, encodes a large protein kinase with a phosphatid ylinositol 3-kinase-like domain. The typical A-T phenotype is caused, in most cases, by null ATM alleles that truncate or severely destabili ze the ATM protein. Rare patients with milder manifestations of the cl inical or cellular characteristics of the disease have been reported a nd have been designated ''A-T variants.'' A special variant form of AT is A-T-Fresno which combines a typical A-T phenotype with microcephal y and mental retardation. The possible association of these syndromes with ATM is both important for understanding their molecular basis and essential for counseling and diagnostic purposes. We quantified ATM-p rotein levels in six A-T variants, and we searched their ATM genes for mutations. Cell lines from these patients exhibited considerable vari ability in radiosensitivity while showing the typical radioresistant D NA synthesis of A-T cells. Unlike classical A-T patients, these patien ts exhibited 1%-17% of the normal level of ATM. The underlying ATM gen otypes were either homozygous for mutations expected to produce mild p henotypes or compound heterozygotes for a mild and a severe mutation. An A-(Fresno) cell line was found devoid of the ATM protein and homozy gous for a severe ATM mutation. We conclude that certain ''A-T variant '' phenotypes represent ATM mutations, including some of those without telangiectasia. Our findings extend the range of phenotypes associate d with ATM mutations.