Skip to main content

Advertisement

SpringerLink
Log in

Basic defect in the expression of adenosine deaminase in ADA- SCID disease investigated through the cells of an obligate heterozygote

  • Original Investigations
  • Published:
Human Genetics Aims and scope Submit manuscript

Summary

The nature of the defect of a female baby who died of severe combined immunodeficiency (SCID) disease associated with adenosine deaminase deficiency (ADA-) was investigated. Since tissue or tissue culture material was not available for subsequent studies, the expression of ADA in her cells was investigated in the somatic cell hybrid clones derived from a fusion between the lymphocytes from one of her two obligate heterozygote parents and thymidine kinase deficient Chinese hamster (a3) fibroblasts. The results of analyses of the human chromosomes and biochemical markers in 12 independent clones and 27 subclones indicated that the ADA deficiency in the patient is determined probably by a mutation in the structural gene for ADA in chromosome 20 leading either to the production of catalytically defective molecules or to the cessation of the production of ADA. Incidentally, the involvement of chromosome 2, which carries a gene for adenosine deaminase complexing protein (ADCP), in the causation of ADA deficiency was excluded. The in vitro approach through the cells from an obligate heterozygote described in this paper may have a general application in pursuing studies on other cases of inborn errors of metabolism whenever the material from the affected individuals (i.e., the homozygotes) is not available or not suitable for direct investigations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Aitken DA, Kleijer WJ, Niermeijer MF, Herbschleb-Voogt E, Galjaard H (1980) Prenatal detection of a probable heterozygote for ADA deficiency and severe combined immunodeficiency disease using a microassay. Clin Genet17:293–298

    Article  CAS  Google Scholar 

  • Blankenstein-Wijnen LMM, Smieder G, Grzeschik KH, Pearson PL, Westerveld A, Meera Khan P (1979) Chromosomal localization of PGP. Cytogenet Cell Genet 25:138

    Google Scholar 

  • Bruns GAP, Gerald PS (1974) Human acid phosphatase in somatic cell hybrids. Science 184:480–482

    Article  CAS  Google Scholar 

  • Cohen F (1975) Clinical features. In: Meuwissen HJ, Pollara B, Pickering RJ, Porter IA (eds) Combined immunodeficiency disease and adenosine deaminase deficiency. Academic Press, New York, p 245

    Google Scholar 

  • Dadonna PE, Kelley WN (1980) Analysis of normal and mutant forms of human adenosine deaminase—A review. Mol Cell Biochem 29:91–101

    Google Scholar 

  • Ebeli-Struijk AC, Wurzer-Figurelli EM, Ajmar F, Meera Khan P (1976) The distribution of esterase D variants in different ethnic groups. Hum Genet 34:299–306

    Article  CAS  Google Scholar 

  • Edwards YH, Hopkinson DA, Harris H (1971) Adenosine deaminase isozymes in human tissues. Ann Hum Genet 35: 207–219

    Article  CAS  Google Scholar 

  • Giblett ER, Anderson JE, Cohen F, Pollara B, Meuwissen HJ (1972) Adenosine-deaminase deficiency in two patients with severe impaired cellular immunity. Lancet II:1067–1069

    Article  Google Scholar 

  • Giblett ER, Scott CP, Chen SH (1975) Adenosine deaminase: genetic aspects. In: Meuwissen HJ, Pollara B, Pickering RJ, Porter IA (eds) Combined immunodeficiency and adenosine deaminase deficiency. Academic Press, New York, p 103

    Google Scholar 

  • Grzeschik KH (1976) Assignment of human genes: β-glucuronidase to chromosome 7, adenylate kinase-1 to 9, a second enzyme with enolase activity to 12 and mitochondrial IDH to 15. Cytogenet Cell Genet 16:142–148

    Article  CAS  Google Scholar 

  • Harris H, Hopkinson DA (1976). In: Handbook of enzyme electrophoresis in Human Genetics. North-Holland Publ Comp. Amsterdam Oxford; American Elsevier Publ Comp Inc, New York

    Google Scholar 

  • Herbschleb-Voogt E, Grzeschik KH, de Wit J, Pearson PL, Meera Khan P (1979) Assignment of a structural gene for adenosine deaminase complexing protein (ADCP) to human chromosome 2 in interspecific somatic cell hybrids. Cytogenet Cell Genet 25:163

    Google Scholar 

  • Herbschleb-Voogt E, Monteba-van Heuvel M, Wijnen LMM, Westerveld A, Pearson PL, Meera Khan P (1978) Chromosomal assignment and regional localization of CS, ENO2, GAPDH, LDHB, PEPB and TPI in man-rodent cell hybrids. Cytogenet Cell Genet 22:482–486

    Article  CAS  Google Scholar 

  • Hirschhorn R (1975) Isozymes of adenosine deaminase. In: Markert CL (ed) Isozymes II. Physiological function. Academic Press, New York, p 583

    Google Scholar 

  • Hirschhorn R, Beratis N, Rosen F (1976) Characterization of residual enzyme activity in fibroblasts from patients with adenosine deaminase deficiency and combined immunodeficiency: Evidence for a mutant enzyme. Proc Natl Acad Sci USA 73:213–217

    Article  CAS  Google Scholar 

  • Hopkinson DA, Cook PJL, Harris H (1969) Further data on the adenosine deaminase polymorphism and a report of a new phenotype. Ann Hum Genet 32:361–367

    Article  CAS  Google Scholar 

  • Hopkinson DA, Povey S, Solomon E, Bobrow M, Gormley IP (1976) Confirmation of the assigment of the locus determining ADA to chromosome 20 in man: data on possible synteny of ADA and ITP in human-Chinese hamster somatic cell hybrids. Cytogenet Cell Genet 16:159–160

    Article  CAS  Google Scholar 

  • Koch GA, Shows TB (1979) Genes on human chromosomes 2 and 6 are required for expression of the adenosine deaminase complexing protein (ADCP) in human-mouse somatic cell hybrids. Cytogenet Cell Genet 25:174

    Google Scholar 

  • Littlefield JW (1966) Selection of hybrids from matings of fibroblasts in vitro and their presumed recombinants. Science 145:709–710

    Article  Google Scholar 

  • Löwenberg B, Vossen JMJJ, Dooren LJ (1977) Transplantation of fetal liver cells in the treatment of severe combined immunodeficiency disease. Blut 34:181–195

    Article  Google Scholar 

  • McKusick VA (1978) In: Mendelian inheritance in man, 5th edn. The Johns Hopkins University Press, Baltimore London, p 400

    Google Scholar 

  • Meera Khan P (1971) Enzyme electrophoresis on cellulose acetate gel: Zymogram patterns in man-mouse and man-Chinese hamster somatic cell hybrids. Arch Biochem Biophys 145:470–483

    Article  CAS  Google Scholar 

  • Meera Khan P, Wijnen LMM, Pearson PL (1978) Assignment of the mitochondrial aconitase gene (ACONM) to human chromosome 22. Cytogenet Cell Genet 22:212–214

    Article  CAS  Google Scholar 

  • Meera Khan P, Pearson PL, Wijnen LMM, Doppert BA, Westerveld A, Bootsma D (1976) Assignment of inosine triphosphatase gene to gorilla chromosome 13 and to human chromosome 20 in primate-rodent somatic cell hybrids. Cytogenet Cell Genet 16:420–421

    Article  CAS  Google Scholar 

  • Meuwissen HJ, Pollara B, Pickering RJ (1975) Combined immunodeficiency disease associated with adenosine deaminase deficiency. J Pediatr 86:169–181

    Article  CAS  Google Scholar 

  • Nadler HL, Egan TJ (1970) Deficiency of lysosomal acid phosphatase. N Engl J Med 282:303–307

    Google Scholar 

  • Nishihara H, Ishikawa S, Shinkai K, Akedo H (1973) Multiple forms of human adenosine deaminase. II. Isolation and properties of a conversion factor from human lung. Biochim Biophys Acta 302:429–442

    Article  CAS  Google Scholar 

  • Pearson PL, van Egmond-Cowan AMM (1976) Further development in banding techniques for mammalian chromosome identification. In: Pain RH, Smith BJ (eds) New techniques in biophysics and cell biology. Wiley, London, p 213

    Google Scholar 

  • Polmar SH (1980) Metabolic aspects of immunodeficiency disease. Semin Hematol 17:30–43

    CAS  PubMed  Google Scholar 

  • Ruddle FH, Creagan RP (1975) Parasexual approaches to the genetics of man. Annu Rev Genet 9:407–468

    Article  CAS  Google Scholar 

  • Siciliano MJ, Bordelon MR, Kohler PO (1978) Expression of human adenosine deaminase after fusion of adenosine deaminase-deficient cells with mouse fibroblasts. Proc Natl Acad Sci USA 75:936–940

    Article  CAS  Google Scholar 

  • Shows TB (1972) Genetics of human-mouse somatic cell hybrids: linkage of human genes for lactate dehydrogenase-A and esterase-A4. Proc Natl Acad Sci USA 69:348–352

    Article  CAS  Google Scholar 

  • van Someren H, Beijersbergen van Henegouwen H, Los W, Wurzer-Figurelli E, Doppert B, Vervloet M, Meera Khan P (1974a) Enzyme electrophoresis on cellulose acetate gel. II: Zymogram patterns in man-Chinese hamster somatic cell hybrids. Hum Genet 25:189–201

    Article  Google Scholar 

  • van Someren H, Westerveld A, Hagemeijer A, Mees JR, Meera Khan P, Zaalberg OB (1974b) Human antigen and enzyme markers in man-Chinese hamster somatic cell hybrids: Evidence for synteny between the HL-A, PGM3, ME1 and IPO-B loci. Proc Natl Acad Sci USA 71:962–965

    Article  Google Scholar 

  • Tischfield JA, Creagan RP, Nichols EA, Ruddle FH (1974) Assignment of a gene for adenosine deaminase to human chromosome 20. Hum Hered 24:1–11

    Article  CAS  Google Scholar 

  • Trotta PP, Smithwick EM, Balis ME (1976) A normal level of adenosine deaminase activity in the red cell lysates of carriers and patients with severe combined immunodeficiency disease. Proc Natl Acad Sci USA 73:104–108

    Article  CAS  Google Scholar 

  • Westerveld A, Visser RPLS, Meera Khan P, Bootsma D (1971) Loss of human genetic markers in man-Chinese hamster somatic cell hybrids. Nature 234:20–24

    CAS  Google Scholar 

  • van der Weyden MB, Kelley WN (1974) Adenosine deaminase deficiency in severe combined immunodeficiency. Evidence for a post-translational defect. J Clin Invest 53:81a

    Google Scholar 

  • Wijnen LMM, Grzeschik KH, Pearson PL, Meera Khan P (1977) The human PGM-2 and its chromosomal localization in man-mouse hybrids. Hum Genet 37:271–278

    Article  CAS  Google Scholar 

  • Wijnen LMM, Monteba-van Heuvel M, Pearson PL, Meera Khan P (1978) Assignment of a gene for glutatione peroxidase (GPX1) to human chromosome 3. Cytogenet Cell Genet 22:232–235

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Human Genetics, State University of Leiden, Wassenaarseweg 72, 2333 AL, Leiden, The Netherlands

    Elly Herbschleb-Voogt, Peter L. Pearson & P. Meera Khan

  2. Department of Pediatrics, University Hospital, Leiden, The Netherlands

    Jaak M. Vossen

Authors
  1. Elly Herbschleb-Voogt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter L. Pearson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jaak M. Vossen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. Meera Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Herbschleb-Voogt, E., Pearson, P.L., Vossen, J.M. et al. Basic defect in the expression of adenosine deaminase in ADA- SCID disease investigated through the cells of an obligate heterozygote. Hum Genet 56, 379–386 (1981). https://doi.org/10.1007/BF00274697

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00274697

Keywords

Search

Navigation