MUTATIONS REVEALED BY SEQUENCING THE 5'-HALF OF THE GENE FOR ATAXIA-TELANGIECTASIA

Ataxia telangiectasia is a recessive disorder in which patients show a progressive cerebellar degeneration leading to ataxia, abnormal eye m ovements and deterioration of speech. Other features include ocular te langiectasia, high serum AFP levels, immunodeficiency, growth retardat ion and an increased predisposition to some tumours, particularly T ce ll leukaemia and lymphoma. We report the 1348 amino acid sequence of t he N-terminal half of the A-T gene product which, together with the pr eviously published C-terminal half, completes the sequence of the A-T protein. No homologies with other genes have been found within the N-t erminal half of the A-T protein. We have also identified six mutations affecting the N-terminal half of the protein. One of these mutations was found to be associated with a haplotype that is common to four app arently unrelated families of Irish descent. All the patients so far e xamined for both A-T alleles were shown to be compound heterozygotes. None of these mutations affected a putative promoter region which may direct divergent transcription of both the A-T gene and a novel gene E 14. The ability to recognise mutations across the entire coding sequen ce of the A-T gene provides a practical advantage to A-T families sinc e a DNA based prenatal diagnosis will be possible in families where th e mutations are identified irrespective of the level of radiosensitivi ty in these families.