The genetic defect in ataxia-telangiectasia

Martin F. Lavin, Yosef Shiloh

Research output: Contribution to journalReview articlepeer-review

Abstract

The autosomal recessive human disorder ataxia-telangiectasia (A-T) was first described as a separate disease entity 40 years ago. It is a multisystem disease characterized by progressive cerebellar ataxia, ocuolocutaneous telangiectasia, radiosensitivity, predisposition to lymphoid malignancies and immunodeficiency, with defects in both cellular and humoral immunity. The pleiotropic nature of the clinical and cellular phenotype suggests that the gene product involved is important in maintaining stability of the genome but also plays a more general role in signal transduction. The chromosomal instability and radiosensitivity so characteristic of this disease appear to be related to defective activation of cell cycle checkpoints. Greater insight into the nature of the defect in A-T has been provided by the recent identification, by positional cloning, of the responsible gene, ATM. The ATM gene is related to a family of genes involved in cellular responses to DNA damage and/or cell cycle control. These genes encode large proteins containing a phosphatidylinosilol 3-kinase domain, some of which have protein kinase activity. The mutations causing A-T completely inactivate or eliminate the ATM protein. This protein has been detected and localized to different subcellular compartments.

Original languageEnglish
Pages (from-to)177-202
Number of pages26
JournalAnnual Review of Immunology
Volume15
DOIs
StatePublished - 1997

Keywords

  • ataxia-telangiectasia
  • cell cycle
  • gene cloning
  • immunodeficiency
  • radiosensitivity

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