Predominance of null mutations in ataxia-telangiectasia

Shlomit Gilad, Rami Khosravi, Dganit Shkedy, Tamar Uziel, Yael Ziv, Kinneret Savitsky, Galit Rotman, Sara Smith, Luciana Chessa, Timothy J. Jorgensen, Reli Harnik, Moshe Frydman, Ozden Sanal, Sima Portnoi, Zipora Goldwicz, N. G.J. Jaspers, Richard A. Gatti, Gilbert Lenoir, Martin F. Lavin, Kouichi TatsumiRolf D. Wegner, Yosef Shiloh, Anat Bar-Shira

Research output: Contribution to journalArticlepeer-review

Abstract

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition. The responsible gene, ATM, was recently identified by positional cloning and found to encode a putative 350 kDa protein with a PI 3-kinase-like domain, presumably involved in mediating cell cycle arrest in response to radiation-induced DNA damage. The nature and location of A-T mutations should provide insight into the function of the ATM protein and the molecular basis of this pleiotropic disease. Of 44 A-T mutations identified by us to date, 39 (89%) are expected to inactivate the ATM protein by truncating it, by abolishing correct initiation or termination of translation, or by deleting large segments. Additional mutations are four smaller in-frame deletions and insertions, and one substitution of a highly conserved amino acid at the PI 3-kinase domain. The emerging profile of mutations causing A-T is thus dominated by those expected to completely inactivate the ATM protein. ATM mutations with milder effects may result in phenotypes related, but not identical, to A-T.

Original languageEnglish
Pages (from-to)433-439
Number of pages7
JournalHuman Molecular Genetics
Volume5
Issue number4
DOIs
StatePublished - Apr 1996

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