Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene

Abstract

X-linked lymphoproliferative syndrome (XLP or Duncan disease) is characterized by extreme sensitivity to Epstein-Barr virus (EBV), resulting in a complex phenotype manifested by severe or fatal infectious mononucleosis, acquired hypogammaglobulinemia and malignant lymphoma. We have identified a gene, SH2D1A, that is mutated in XLP patients and encodes a novel protein composed of a single SH2 domain. SH2D1A is expressed in many tissues involved in the immune system. The identification of SH2D1A will allow the determination of its mechanism of action as a possible regulator of the EBV-induced immune response.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Physical map of the XLP critical region.
Figure 2: Human SH2D1A gene.
Figure 3: Expression of SH2D1A.
Figure 4: Analysis of SH2D1A in an XLP family.

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. 1

    Epstein, M.A., Achong, B.G. & Barr, Y.M. Virus particles in cultured lymphocytes from Burkitt's lymphoma. Lancet 1, 702– 703 (1964).

    CAS  Article  Google Scholar 

  2. 2

    zur Hausen, H. et al. EBV DNA in biopsies of Burkitt's tumours and anaplastic carcinoma of the nasopharynx. Nature 228, 1056–1058 (1970).

    CAS  Article  Google Scholar 

  3. 3

    Imai, S. et al. Gastric carcinoma: Monoclonal epithelial malignant cells expressing Epstein-Barr virus latent infection protein. Proc. Natl Acad. Sci. USA 91, 9131–9135 ( 1994).

    CAS  Article  Google Scholar 

  4. 4

    Klein, G. The Epsein-Barr virus and neoplasia. N. Engl. J. Med. 293, 1353–1357 (1975).

    CAS  Article  Google Scholar 

  5. 5

    McClain, K.L. et al. Association of Epstein-Barr virus with leiomyosarcomas in young people with AIDS. N. Engl. J. Med. 332, 12–18 (1995).

    CAS  Article  Google Scholar 

  6. 6

    Rickinson, A.B., Lee, S.P. & Steven, N.M. Cytotoxic T lymphocyte responses to Epstein-Barr virus. Curr. Opin. Immunol. 8, 492– 497 (1996).

    CAS  Article  Google Scholar 

  7. 7

    Purtilo, D.T. et al. X-linked recessive progressive combined variable immunodeficiency (Duncan's disease). Lancet 1, 935– 940 (1975).

    CAS  Article  Google Scholar 

  8. 8

    Purtilo, D.T., Grierson, H.L., Davis, J.R. & Okano, M. The X-linked lymphoproliferative disease: from autopsy toward cloning the gene, 1975-1990. Pediatr. Pathol. 11, 685 –710 (1991).

    CAS  Article  Google Scholar 

  9. 9

    Harrington, D.S., Weisenburger, D.D. & Purtilo, D.T. Malignant lymphoma in the X-linked Lymphoproliferative Syndrome. Cancer 59, 1419– 1429 (1987).

    CAS  Article  Google Scholar 

  10. 10

    Weisenburger, D.D. & Purtilo, D.T. Failure in immunological control of the virus infection: fatal infectious mononucleosis. in The Epstein-Barr Virus: Recent Advances (eds Epstein, M.A. & Achong, B.G.) 129–161 (Heinmann Medical Books, London, England, 1986).

    Google Scholar 

  11. 11

    Skare, J.C. et al.. Linkage analysis of seven kindreds with the X-linked lymphoproliferative syndrome (XLP) confirms that the XLP locus is near DXS42 and DXS37. Hum. Genet. 82, 354– 358 (1989).

    CAS  PubMed  Google Scholar 

  12. 12

    Wyandt, H.E. et al. Chromosomal deletion of Xq25 in an individual with X-linked lymphoproliferative disease. Am. J. Hum. Genet. 33, 426–430 (1989).

    CAS  Article  Google Scholar 

  13. 13

    Sanger, W.G. et al. Partial Xq25 deletion in a family with the X-linked lymphoproliferative disease (XLP). Cancer Genet. Cytogenet. 47, 163–169 (1990).

    CAS  Article  Google Scholar 

  14. 14

    Skare, J.C. et al. cterization of three overlapping deletions causing X-linked lymphoproliferative disease. Genomics 16, 254–255 (1993).

    CAS  Article  Google Scholar 

  15. 15

    Wu, B.L. et al. High-resolution mapping of probes near the X-linked lymphoproliferative disease (XLP) locus. Genomics 17, 163– 170 (1993).

    CAS  Article  Google Scholar 

  16. 16

    Coulson, A. et al. Towards a physical map of the genome of nematode C. elegans. Proc. Natl Acad. Sci. USA 83, 7821– 7825 (1996).

    Article  Google Scholar 

  17. 17

    Gregory, S.G., Howell, G.R. & Bentley, D.R. Genome mapping by fluorescent fingerprinting. Genome Res. 7, 1162–1168 (1997).

    CAS  Article  Google Scholar 

  18. 18

    Liston, P. et al. Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature 379, 349–353 (1996).

    CAS  Article  Google Scholar 

  19. 19

    Bolino, A. et al. A new candidate region for the positional cloning of the XLP gene. Eur. J. Hum. Genet. in press.

  20. 20

    Ware, M.D. et al. Cloning and characterisation of the human SHIP, the 145-kD inositol 5-phosphatase that associates with SHC after cytokine stimulation. Blood 88, 2833–2840 (1996).

    CAS  PubMed  Google Scholar 

  21. 21

    Pesesse, X., Deleu, S., De Smedt, F., Drayer, L. & Erneux, C. Identification of a second SH2-domain-containing protein closely related to the phosphatidylinositol polyphosphate 5-phosphatase SHIP. Biochem. Biophys. Res. Commun. 239, 697 –700 (1997).

    CAS  Article  Google Scholar 

  22. 22

    Thompson, A.D. et al. EAT-2 is a novel SH2 domain containing protein that is up regulated by Ewing's sarcoma EWS/FL11 fusion gene. Oncogene 13, 2649–2658 ( 1996).

    CAS  PubMed  Google Scholar 

  23. 23

    Fainstein, E. et al. Nucleotide sequence analysis of human abl and bcr-abl cDNAs. Oncogene 4, 1477–1481 (1989).

    CAS  PubMed  Google Scholar 

  24. 24

    Huang, S-H., Jong, A.Y., Yang, W. & Holcenberg, J. Amplification of gene ends from gene libraries by polymerase chain reaction with single-sided specificity. in Methods in Molecular Biology, PCR Protocols: Current Methods and Applications (ed White B.A.) 357– 363 (Humana Press, Totowa, New Jersey, 1993).

    Google Scholar 

  25. 25

    Riley, J. et al. A novel, rapid method for the isolation of terminal sequences from yeast artificial chromosome (YAC) clones. Nucleic Acids Res. 18, 2887–2890 ( 1990).

    CAS  Article  Google Scholar 

  26. 26

    Roberts, R.G., Coffey, A.J., Bobrow, M. & Bentley, D.R. Exon structure of the human dystrophin gene. Genomics 16, 536–538 (1993).

    CAS  Article  Google Scholar 

  27. 27

    Bhat. N.K. et al. Reciprocal expression of human ETS1 and ETS2 genes during T-cell activation: regulatory role for the protooncogene ETS1. Proc. Natl Acad. Sci. USA 87, 3723– 3727 (1990).

    CAS  Article  Google Scholar 

  28. 28

    Songyang, Z. et al. SH2 domains recognize specific phosphopeptide sequences. Cell 72, 767–778 ( 1993).

    CAS  Article  Google Scholar 

  29. 29

    Kuriyan, J. & Cowburn, D. Structures of SH2 and SH3 domains. Curr. Opin. Struct. Biol. 3, 828– 837 (1993).

    CAS  Article  Google Scholar 

  30. 30

    Mayer, B.J., Jackson, P.K., Van Etten, R.A. & Baltimore, D. Point mutations in the abl SH2 domain coordinately impair phosphotyrosine binding in vitro and transforming activity in vivo. Mol. Cell. Biol. 12, 609–618 (1992).

    CAS  Article  Google Scholar 

  31. 31

    Lamartine, J. et al. Physical map and cosmid contig encompassing a new interstitial deletion of the X-linked lymphoproliferative syndrome region. Eur. J. Hum. Genet. 4, 342–351 (1996).

    CAS  Article  Google Scholar 

  32. 32

    Lanyi, A. et al. A yeast artificial chromosome (YAC) contig encompassing the critical region of the X-linked lymphoproliferative disease (XLP) locus. Genomics 39, 55–65 ( 1997).

    CAS  Article  Google Scholar 

  33. 33

    Arkwright, P.D. et al. X-linked lymphoproliferative disease in a UK family. Archives Dis. Childh. in press.

  34. 34

    Shapiro, M.B. & Senapathy, P. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res. 15, 7155–7174 (1987).

    CAS  Article  Google Scholar 

  35. 35

    Schuster, V. et al. Molecular genetic haplotype segregation studies in three families with X-linked lymphoproliferative disease. Eur. J. Pediatr. 153, 432–437 ( 1994).

    CAS  Article  Google Scholar 

  36. 36

    Koch, C.A., Anderson, D., Moran, M.F., Ellis, C. & Pawson, T. SH2 and SH3 Domains: Elements that control interactions of cytoplasmic signaling proteins. Science 252, 668–673 ( 1991).

    CAS  Article  Google Scholar 

  37. 37

    Chan, A.C., Irving, B.A., Fraser, /FNM> & Weiss, A. The ζ chain is associated with a tyrosine kinase and upon T-cell antigen receptor stimulation associates with ZAP-70, a 70-kDa tyrosine phosphoprotein. Proc. Natl Acad. Sci. USA 88, 9166–9170 (1991).

    CAS  Article  Google Scholar 

  38. 38

    Ono, M., Bolland, S., Tempst, P. & Ravetch, J.V. Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor FcγRIIB. Nature 383, 263– 266 (1996).

    CAS  Article  Google Scholar 

  39. 39

    Levine, A. et al. odd Oz: A novel drosophila pair rule gene. Cell 77, 587–598 ( 1994).

    CAS  Article  Google Scholar 

  40. 40

    Williams, L.L. et al. Correction of Duncan's syndrome by allogeneic bone marrow transplantation. Lancet 342, 587– 588 (1993).

    CAS  Article  Google Scholar 

  41. 41

    Filipovich, A. et al. Allogenic bone marrow transplantation for X-linked lymphoproliferative syndrome. Transplantation 42, 222– 224 (1986).

    CAS  PubMed  Google Scholar 

  42. 42

    Vowels, M.R. et al. Correction of X-linked lymphoproliferative disease by transplantation of cord-blood stem cells. N. Engl. J. Med. 329, 1623–1625 (1993).

    CAS  Article  Google Scholar 

  43. 43

    Larin, Z., Monaco, A.P. & Lehrach, H. Yeast artificial chromosome libraries containing large inserts from mouse and human DNA. Proc. Natl Acad. Sci. USA 88, 4123–4127 (1991).

    CAS  Article  Google Scholar 

  44. 44

    Anand, R., Villasante, A. & Tyler-Smith, C. Construction of yeast artificial chromosome libraries with large inserts using fractionation by pulsed-field gel electrophoresis. Nucleic Acids Res. 17, 3425– 3433 (1989).

    CAS  Article  Google Scholar 

  45. 45

    Albersten, H.M. et al. Construction and characterisation of a yeast artificial chromosome library containing seven haploid human genome equivalents. Proc. Natl Acad. Sci. USA 87, 425– 460 (1990).

    Google Scholar 

  46. 46

    Soderlund, C. & Dunham, I. SAM: a system for iteratively building marker maps. Comput. Appl. Biosci. 11, 645 –655 (1995).

    CAS  PubMed  Google Scholar 

  47. 47

    Coffey, A.J. et al. Construction of a 2.6 Mb contig in yeast artificial chromosomes spanning the human dystrophin gene using an STS-based approach. Genomics 12, 474–484 ( 1992).

    CAS  Article  Google Scholar 

  48. 48

    Uberbacher, E.C. & Mural, R.J. Locating protein-coding regions in human DNA sequences by a multiple sensor-neural network approach. Proc. Natl Acad. Sci. USA 88, 11261– 11265 (1991).

    CAS  Article  Google Scholar 

  49. 49

    Burge, C. & Karlin, S. Prediction of complete gene structures in human genomic DNA. J. Mol. Biol. 1, 78 –94 (1997).

    Article  Google Scholar 

  50. 50

    Solovyev, V.V., Salamov, A.A. & Lawrence, C.B. Identification of human gene structure using linear discriminant functions and dynamic programming. Ismb 3, 367–375 (1995).

    CAS  PubMed  Google Scholar 

  51. 51

    Church, D.M. et al. Isolation of genes from complex sources of mammalian genomic DNA using exon amplification. Nature Genet. 6, 98–105 (1994).

    CAS  Article  Google Scholar 

  52. 52

    Burn, T.C., Connors, T.D., Klinger, K.W. & Landes, G.M. Increased exon-trapping efficiency through modifications to the pSPL3 splicing vector. Gene 161, 183–187 (1995).

    CAS  Article  Google Scholar 

  53. 53

    Frohman, M.A. Dush, M.K. & Martin, G.T. Rapid production of full-length cDNAs from rare transcripts: amplification using a single gene-specific oligonucleotide primer. Proc. Natl Acad. Sci. USA 85, 8998– 9002 (1988).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank the patients, families and physicians who have contributed to this project. We thank all the members of Team 32 at the Sanger Centre for all the genomic sequencing. We also thank E. Campbell and T. Freeman for help with expression profiling, L. Everett for isolation of a BAC clone, S. Abbs and D. Vetrie for the provision of normal DNA samples, E. Sotheran, R. Gwilliam, D. Pearson, J. Conquer, P. Hunt and C. Cole for clone resources, D. Simmons for the gift of cDNA libraries, L. Webb for provision of B cell cDNA, R. Guy for T cells, H. Chapel, D. Crawford and Donhuisen-Ant for provision of patient material, A. Rickinson for helpful discussions and I. Dunham for critical review of the manuscript. We gratefully acknowledge the support of the Wellcome Trust. O.B. has been supported by the German Federal Ministery for Education, Research and Technology. G.P. was supported by Telethon 633 and AIRC. J.S. is supported by HIH grant NIH-NIAD 1 R01 AI33532-OIA3. M.S. is supported by a grant from TELETHON Italy. G.R. and L.Y. are supported by a grant from ARC. The continuous support of the Williams C. Havens Foundation to this project is acknowledged.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Alison J. Coffey or Robert A. Brooksbank.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Coffey, A., Brooksbank, R., Brandau, O. et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat Genet 20, 129–135 (1998). https://doi.org/10.1038/2424

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing