Adenosine deaminase (ADA) deficiency due to deletion of the ADA gene promoter and first exon by homologous recombination between two alu elements

• Published in: The Journal of clinical investigation 1988-05, Vol.81 (5), p.1323-1327
• Main Authors: MARKERT, M. L, HUTTON, J. J, WIGINTON, D. A, STATES, J. C, KAUFMAN, R. E
• Format: Article
• Language: English
• Subjects: Adenosine Deaminase - deficiency; Adenosine Deaminase - genetics; Base Sequence; Biological and medical sciences; Chromosome Deletion; Cloning, Molecular; DNA - genetics; Exons; Humans; Immunologic Deficiency Syndromes - genetics; Male; Medical genetics; Medical sciences; Molecular Sequence Data; Mutation; Nucleic Acid Hybridization; Nucleoside Deaminases - deficiency; Promoter Regions, Genetic; Recombination, Genetic; Repetitive Sequences, Nucleic Acid; Sequence Homology, Nucleic Acid
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI113458

In 15-20% of children with severe combined immunodeficiency (SCID), the underlying defect is adenosine deaminase (ADA) deficiency. The goal of this study was to determine the precise molecular defect in a patient with ADA-deficient SCID whom we previously have shown to have a total absence of ADA mRNA and a structural alteration of the ADA gene. By detailed Southern analysis, we now have determined that the structural alteration is a deletion of approximately 3.3 kb, which included exon 1 and the promoter region of the ADA gene. DNA sequence analysis demonstrates that the deletion created a novel, complete Alu repeat by homologous recombination between two existing Alu repeats that flanked the deletion. The 26-bp recombination joint in the Alu sequence includes the 10-bp "B" sequence homologous to the RNA polymerase III promoter. This is the first example of homologous recombination involving the B sequence in Alu repeats. Similar recombination events have been identified involving Alu repeats in which the recombination joint was located between the A and B sequences of the polymerase III split promoter. The nonrandom location of these events suggests that these segments may be hot spots for recombination.