Phenotypic Complementation of Cells from Human Hereditary Diseases with Defects in Cellular Responses to DNA Damage, by Single Human Chromosomes

  • Karla A. Henning
  • Clare Lambert
  • Roger A. Schultz
  • Errol C. Friedberg


A better understanding of the molecular basis of human hereditary disease could be reached by the isolation and characterization of the genes involved. Some studies have approached this problem through genetic linkage analysis: localizing the gene to a particular area of a chromosome and then using techniques such as chromosome walking to identify the gene of interest. This type of analysis is time consuming and labor intensive, and requires access to large numbers of affected families and suitable DNA probes. Certain hereditary diseases offer an alternative approach for gene cloning because they exhibit correctable phenotypes in cultured cells. For example, xeroderma pigmentosum (XP), ataxia telangiectasia (AT), Cockayne’s syndrome and Fanconi’s anemia all display hypersensitivity to various DNA-damaging agents which can be complemented in vitro (1). Unfortunately, attempts to clone these genes through the technique of DNA transfection have met with little success, probably due to the inefficiency of human cells in the uptake and stable expression of large amounts of exogenous DNA (2-4).


Spinal Muscular Atrophy Ataxia Telangiectasia Xeroderma Pigmentosum Ataxia Telangiectasia Complementation Group 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    E. C. Friedberg, DNA damage and human disease. In: “DNA Repair,” pp. 505–574. W. H. Freeman, New York, 1985.Google Scholar
  2. 2.
    H. Lohrer, M. Blum, and P. Herrlich, Ataxia telangiectasia resists gene cloning: An account of parameters determining gene transfer into recipient cells. Mol. Gen. Genet. 212. 474–480 (1988).PubMedCrossRefGoogle Scholar
  3. 3.
    L. V. Mayne, T. Jones, S.W. Dean, 5. A. Harcourt, J. E. Lowe, A. Priestly, H. Steingrinsdotter, H. Sykes, M. H. L. Green, and A. R. Lehmann, SV40-transformed normal and DNA-repair-deficient human fibroblasts can be transfected with high frequency but retain only limited amounts of integrated DNA. Gene 66, 65–76 (1988).PubMedCrossRefGoogle Scholar
  4. 4.
    M. M. Gebara, C. Drevon, 5. A. Harcourt, H. Steingrinsdotter, M. R. James, J. F. Burke, C. F. Arlett, and A. R. Lehmann, Inactivation of a transfected gene in human fibroblasts can occur by deletion, amplification, phenotypic switching, or methylation. Mol. Cell. Biol. 7, 1459–1464 (1987).PubMedGoogle Scholar
  5. 5.
    P. J. Saxon, E. 5. Srivatsan, G. V. Leipzig, J. H. Sameshima, and E. J. Stanbridge, Selective transfer of individual human chromosomes to recipient cells. Mol. Cell. Biol. 5, 140–146 (1985).PubMedGoogle Scholar
  6. 6.
    P. J. Saxon and E. J. Stanbridge, Transfer and selective retention of single specific human chromosomes via microcell-mediated chromosome transfer. Methods Enzymol. 151, 313–325 (1987).PubMedCrossRefGoogle Scholar
  7. 7.
    K. Tanaka, I. Satokata, Z. Ogita, T. Uchida, and Y. Okada, Molecular cloning of a mouse DNA repair gene that complements the defect of group-A xeroderma pigmentosum. Proc. Natl. Acad. Sci. USA 86, 5512–5516 (1989).PubMedCrossRefGoogle Scholar
  8. 8.
    P. J. Southern and P. Berg, Transformation of mammalian cells to antibiotic resistance with a bacterial gene under control of the SV40 early region promoter. J. Mol. Avpl. Genet. 1, 327–341 (1982).Google Scholar
  9. 9.
    J. E. Cleaver, DNA repair in man. Birth Defects 25, 61–82 (1989).PubMedGoogle Scholar
  10. 10.
    R. B. Painter, Altered DNA synthesis in irradiated and unirradiated ataxia telangiectasia cells. In: “Ataxia Telangiectasia: Genetics, Neuropathology, and Immunology of a Degenerative Disease of Childhood” (R. A. Gatti and M. Swift, Eds.), pp. 89–100. Alan Liss Inc., New York, 1985.Google Scholar
  11. 11.
    N. G. Jaspers, R. A. Gatti, C. Baan, P. C. Linssen, and D. Bootsma, Genetic complementation analysis of ataxia telangiectasia and Nijmegen breakage syndrome: a survey of 50 patients. Cytogenet. Cell. Genet. 49, 259–263 (1988).PubMedCrossRefGoogle Scholar
  12. 12.
    J. E. Cleaver, Xeroderma pigmentosum. In: “The Metabolic Basis of Inherited Disease” (J. B. Stanbury, J. B. Wyngaarden, D. S. Fredrickson, J. S. Goldstein and M. S. Brown, Eds.), pp. 1227–1248. McGraw-Hill, New York, 1983.Google Scholar
  13. 13.
    K. H. Kraemer and H. Slor, Xeroderma pigmentosum. Clin. Dermatol. 3, 33–69 (1985).PubMedCrossRefGoogle Scholar
  14. 14.
    R. T. Johnson, G. C. Elliott, S. Squires, and V. C. Joysey, Lack of complementation between xeroderma pigmentosum complementation groups D and H. Hum. Genet. 81, 203–210 (1989).Google Scholar
  15. 15.
    D. Bootsma, W. Keijzer, E. G. Jung, and E. Bohnert, Xeroderma pigmentosum complementation group XP-I withdrawn. Mutat. Res. 218, 149–151 (1989).PubMedCrossRefGoogle Scholar
  16. 16.
    P. J. Saxon, R. A. Schultz, E. J. Stanbridge, and E. C. Friedberg, Human chromosome 15 confers partial complementation of phenotypes to xeroderma pigmentosum group F cells. Am. J Hum. Genet. 44, 474–485 (1989).PubMedGoogle Scholar
  17. 17.
    R. A. Schultz, P. J. Saxon, T. W. Glover, and E. C. Friedberg, Microcell-mediated transfer of a single human chromosome complements xeroderma pigmentosum group A fibroblasts. Proc. Natl. Acad. Sci. USA 84, 4176–4179 (1987).PubMedCrossRefGoogle Scholar
  18. 18.
    K. A. Henning, R. A. Schultz, G.S. Sekhon, and E. C. Friedberg, A gene which complements xeroderma pigmentosum group A cells maps to human chromosome 9q22.2-q34.3. Somatic Cell Mol. Genet. 16, 395–400 (1990).CrossRefGoogle Scholar
  19. 19.
    G. P. Kaur and R. S Athwal, Complementation of a DNA repair defect in xeroderma pigmentosum cells by transfer of human chromosome 9. Proc. Natl. Acad. Sci. USA 86, 8872–8876 (1989).PubMedCrossRefGoogle Scholar
  20. 20.
    R. A. Schultz, P. J. Saxon, T. W. Glover, E. J. Stanbridge, and E. C. Friedberg, Phenotypic complementation of xeroderma pigmentosum cells by transfer of single human chromosomes. In: “Mechanisms and Consequences of DNA Damage Processing” (E. C. Friedberg and P. C. Hanawalt, Eds.), pp. 343–348. Alan R. Liss, Inc., New York, 1988.Google Scholar
  21. 21.
    M. Swift, D. Morrell, E. Cromartie, A. R. Chamberlain, M. H. Skolnick, and D. T. Bishop, The incidence and gene frequency of ataxia-telangiectasia in the United States. Am. J. Hum. Genet. 39, 573–583 (1986).PubMedGoogle Scholar
  22. 22.
    E. C. Pippard, A. J. Hall, D. J. Barker, and B. A. Bridges, Cancer in homozygotes and heterozygotes of ataxia-telangiectasia and xeroderma pigmentosum in Britain. Cancer Res. 48, 2929–2932 (1988).PubMedGoogle Scholar
  23. 23.
    M. Swift, C. L. Chase, and D. Morrell, Cancer predisposition of ataxia-telangiectasia heterozygotes. Cancer Genet. Cytogenet. 46, 21–27 (1990).PubMedCrossRefGoogle Scholar
  24. 24.
    E. Boder, Ataxia-telangiectasia: An overview. In: “Ataxia-telangiectasia: Genetics, Neuropathology, and Immunology of a Degenerative Disease of Childhood” (R. A. Gatti and M. Swift, Eds.), pp. 1–63. Alan Liss Inc., New York, 1985.Google Scholar
  25. 25.
    B. D. Spector, A. H. Filopovich, G. S. Perry III, and J. H. Kersey, In: “Ataxia telangiectasia: A cellular and Molecular Link Between Cancer, Neuropathology, and Immune Deficiency” (R. A. Gatti and M. Swift, Eds.), pp. 103–138. J. Wiley and Sons, New York, 1982.Google Scholar
  26. 26.
    D. Morrell, E. Cromartie, and M. Swift, Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. J. Natl. Cancer Inst. 77, 89–92 (1986).PubMedGoogle Scholar
  27. 27.
    R. Abadir and N. Hakami, Ataxia telangiectasia with cancer. An indication for reduced radiotherapy and chemotherapy doses. Br. J. Radiol. 56, 343–345 (1983).PubMedCrossRefGoogle Scholar
  28. 28.
    M. C. Paterson and P. J. Smith, Ataxia telangiectasia: an inherited human disorder involving hypersensitivity to ionizing radiation and related DNA-damaging chemicals. Annu. Rev. Genet. 13, 291–318 (1979).PubMedCrossRefGoogle Scholar
  29. 29.
    Y. Shiloh, E. Tabor, and Y. Becker, In vitro phenotype of AT fibroblast strains: clues to the nature of the “AT DNA lesion” and the molecular defect in AT. In: “Ataxia Telangiectasia: Genetics, Neuropathology, and Immunology of a Degenerative Disease of Childhood” (R. A. Gatti and M. Swift, Eds.), pp. 111–121. Alan Liss Inc., New York, 1985.Google Scholar
  30. 30.
    R. A. Gatti, I. Berkel, E. Boder, G. Braedt, P. Charmley, P. Concannon, F. Ersoy, T. Foroud, N. G. J. Jaspers, K. Lange, G. M. Lathrop, M. Leppert, Y. Nakamura, P. O’Connell, M. Patterson, W. Salser, O. Sanal, J. Silver, R. S. Sparkes, E. Susi, D. E. Weeks, S. Wei, R. White, and F. Yoder, Localization of an ataxia-telangiectasia gene to chromosome 11q22–23. Nature 336, 577–580 (1988).PubMedCrossRefGoogle Scholar
  31. 31.
    C. Lambert, R. A. Schultz, M. Smith, C. Wagner-McPherson, L. D. McDaniel, T. Donlon, E. J. Stanbridge and E. C. Friedberg, Functional complementation of ataxia-telangiectasia group D cells by microcell-mediated chromosome transfer and mapping of the AT-D locus to the region 11q22–23. Proc. Natl. Acad. Sci. USA (in press).Google Scholar

Copyright information

© Springer Science+Business Media New York 1991

Authors and Affiliations

  • Karla A. Henning
    • 1
  • Clare Lambert
    • 1
  • Roger A. Schultz
    • 1
  • Errol C. Friedberg
    • 1
  1. 1.Department of PathologyStanford University School of MedicineStanfordUSA

Personalised recommendations