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. 1988 May;81(5):1323–1327. doi: 10.1172/JCI113458

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

M L Markert 1, J J Hutton 1, D A Wiginton 1, J C States 1, R E Kaufman 1
PMCID: PMC442559  PMID: 3366897

Abstract

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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adrian G. S., Wiginton D. A., Hutton J. J. Structure of adenosine deaminase mRNAs from normal and adenosine deaminase-deficient human cell lines. Mol Cell Biol. 1984 Sep;4(9):1712–1717. doi: 10.1128/mcb.4.9.1712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Benton W. D., Davis R. W. Screening lambdagt recombinant clones by hybridization to single plaques in situ. Science. 1977 Apr 8;196(4286):180–182. doi: 10.1126/science.322279. [DOI] [PubMed] [Google Scholar]
  3. Bonthron D. T., Markham A. F., Ginsburg D., Orkin S. H. Identification of a point mutation in the adenosine deaminase gene responsible for immunodeficiency. J Clin Invest. 1985 Aug;76(2):894–897. doi: 10.1172/JCI112050. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bortin M. M., Rimm A. A. Severe combined immunodeficiency disease. Characterization of the disease and results of transplantation. JAMA. 1977 Aug 15;238(7):591–600. [PubMed] [Google Scholar]
  5. Brunner A. M., Schimenti J. C., Duncan C. H. Dual evolutionary modes in the bovine globin locus. Biochemistry. 1986 Sep 9;25(18):5028–5035. doi: 10.1021/bi00366a009. [DOI] [PubMed] [Google Scholar]
  6. Buckley R. H., Schiff S. E., Sampson H. A., Schiff R. I., Markert M. L., Knutsen A. P., Hershfield M. S., Huang A. T., Mickey G. H., Ward F. E. Development of immunity in human severe primary T cell deficiency following haploidentical bone marrow stem cell transplantation. J Immunol. 1986 Apr 1;136(7):2398–2407. [PubMed] [Google Scholar]
  7. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  8. Deininger P. L., Jolly D. J., Rubin C. M., Friedmann T., Schmid C. W. Base sequence studies of 300 nucleotide renatured repeated human DNA clones. J Mol Biol. 1981 Sep 5;151(1):17–33. doi: 10.1016/0022-2836(81)90219-9. [DOI] [PubMed] [Google Scholar]
  9. Galli G., Hofstetter H., Birnstiel M. L. Two conserved sequence blocks within eukaryotic tRNA genes are major promoter elements. Nature. 1981 Dec 17;294(5842):626–631. doi: 10.1038/294626a0. [DOI] [PubMed] [Google Scholar]
  10. Giblett E. R., Anderson J. E., Cohen F., Pollara B., Meuwissen H. J. Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity. Lancet. 1972 Nov 18;2(7786):1067–1069. doi: 10.1016/s0140-6736(72)92345-8. [DOI] [PubMed] [Google Scholar]
  11. Ingolia D. E., Al-Ubaidi M. R., Yeung C. Y., Bigo H. A., Wright D., Kellems R. E. Molecular cloning of the murine adenosine deaminase gene from a genetically enriched source: identification and characterization of the promoter region. Mol Cell Biol. 1986 Dec;6(12):4458–4466. doi: 10.1128/mcb.6.12.4458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Katsuki T., Hinuma Y. Characteristics of cell lines derived from human leukocytes transformed by different strains of Epstein-Barr virus. Int J Cancer. 1975 Feb 15;15(2):203–210. doi: 10.1002/ijc.2910150205. [DOI] [PubMed] [Google Scholar]
  13. Lehrman M. A., Russell D. W., Goldstein J. L., Brown M. S. Alu-Alu recombination deletes splice acceptor sites and produces secreted low density lipoprotein receptor in a subject with familial hypercholesterolemia. J Biol Chem. 1987 Mar 5;262(7):3354–3361. [PubMed] [Google Scholar]
  14. Markert M. L., Hershfield M. S., Schiff R. I., Buckley R. H. Adenosine deaminase and purine nucleoside phosphorylase deficiencies: evaluation of therapeutic interventions in eight patients. J Clin Immunol. 1987 Sep;7(5):389–399. doi: 10.1007/BF00917017. [DOI] [PubMed] [Google Scholar]
  15. Markert M. L., Hershfield M. S., Wiginton D. A., States J. C., Ward F. E., Bigner S. H., Buckley R. H., Kaufman R. E., Hutton J. J. Identification of a deletion in the adenosine deaminase gene in a child with severe combined immunodeficiency. J Immunol. 1987 May 15;138(10):3203–3206. [PubMed] [Google Scholar]
  16. Nicholls R. D., Fischel-Ghodsian N., Higgs D. R. Recombination at the human alpha-globin gene cluster: sequence features and topological constraints. Cell. 1987 May 8;49(3):369–378. doi: 10.1016/0092-8674(87)90289-3. [DOI] [PubMed] [Google Scholar]
  17. Orkin S. H., Daddona P. E., Shewach D. S., Markham A. F., Bruns G. A., Goff S. C., Kelley W. N. Molecular cloning of human adenosine deaminase gene sequences. J Biol Chem. 1983 Nov 10;258(21):12753–12756. [PubMed] [Google Scholar]
  18. Paolella G., Lucero M. A., Murphy M. H., Baralle F. E. The Alu family repeat promoter has a tRNA-like bipartite structure. EMBO J. 1983;2(5):691–696. doi: 10.1002/j.1460-2075.1983.tb01486.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Rinehart F. P., Ritch T. G., Deininger P. L., Schmid C. W. Renaturation rate studies of a single family of interspersed repeated sequences in human deoxyribonucleic acid. Biochemistry. 1981 May 26;20(11):3003–3010. doi: 10.1021/bi00514a003. [DOI] [PubMed] [Google Scholar]
  20. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  21. Valerio D., Dekker B. M., Duyvesteyn M. G., van der Voorn L., Berkvens T. M., van Ormondt H., van der Eb A. J. One adenosine deaminase allele in a patient with severe combined immunodeficiency contains a point mutation abolishing enzyme activity. EMBO J. 1986 Jan;5(1):113–119. doi: 10.1002/j.1460-2075.1986.tb04184.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Valerio D., Duyvesteyn M. G., Dekker B. M., Weeda G., Berkvens T. M., van der Voorn L., van Ormondt H., van der Eb A. J. Adenosine deaminase: characterization and expression of a gene with a remarkable promoter. EMBO J. 1985 Feb;4(2):437–443. doi: 10.1002/j.1460-2075.1985.tb03648.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Valerio D., Duyvesteyn M. G., Meera Khan P., Geurts van Kessel A., de Waard A., van der Eb A. J. Isolation of cDNA clones for human adenosine deaminase. Gene. 1983 Nov;25(2-3):231–240. doi: 10.1016/0378-1119(83)90227-5. [DOI] [PubMed] [Google Scholar]
  24. Wiginton D. A., Adrian G. S., Friedman R. L., Suttle D. P., Hutton J. J. Cloning of cDNA sequences of human adenosine deaminase. Proc Natl Acad Sci U S A. 1983 Dec;80(24):7481–7485. doi: 10.1073/pnas.80.24.7481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Wiginton D. A., Kaplan D. J., States J. C., Akeson A. L., Perme C. M., Bilyk I. J., Vaughn A. J., Lattier D. L., Hutton J. J. Complete sequence and structure of the gene for human adenosine deaminase. Biochemistry. 1986 Dec 16;25(25):8234–8244. doi: 10.1021/bi00373a017. [DOI] [PubMed] [Google Scholar]

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