Predominance of null mutations in ataxia-telangiectasia - PubMed (original) (raw)

doi: 10.1093/hmg/5.4.433.

R Khosravi, D Shkedy, T Uziel, Y Ziv, K Savitsky, G Rotman, S Smith, L Chessa, T J Jorgensen, R Harnik, M Frydman, O Sanal, S Portnoi, Z Goldwicz, N G Jaspers, R A Gatti, G Lenoir, M F Lavin, K Tatsumi, R D Wegner, Y Shiloh, A Bar-Shira

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Predominance of null mutations in ataxia-telangiectasia

S Gilad et al. Hum Mol Genet. 1996 Apr.

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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 Pl 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 Pl 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.

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