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

Nature Geneticsvolume 20, pages129–135 (1998)Cite this article

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.SH2D1Ais expressed in many tissues involved in the immune system. The identification ofSH2D1A will allow the determination of its mechanism of action as a possible regulator of the EBV-induced immune response.

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Figure 1: Physical map of the XLP critical region.
Figure 2: HumanSH2D1A gene.
Figure 3: Expression ofSH2D1A.
Figure 4: Analysis ofSH2D1A in an XLP family.

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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.

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Authors and Affiliations

  1. The Sanger Centre, Wellcome Trust Genome Campus, Hinxton,, CB10 1SA, Cambridgeshire, UK

    Alison J. Coffey, Robert A. Brooksbank, Gareth R. Howell, Jacqueline M. Bye, Anthony P. Cahn, Jillian Durham, Paul Heath, Paul Wray, Rebecca Pavitt, Jane Wilkinson, Margaret Leversha, Elizabeth Huckle, Charles J. Shaw-Smith, Andrew Dunham, Susan Rhodes, Mark Vaudin, Mark T. Ross & David R. Bentley

  2. Abt. Medizinische Genetik der LMU, Goethestraße 29, Munich, 80336, Germany

    Oliver Brandau, Helene Achatz, Jan Murken & Alfons Meindl

  3. Max Planck-Institut für Biochemie, Martinsried, 82152, Germany

    Toshitaka Oohashi & Reinhard Fassler

  4. Dept of Respiratory Medicine, Addenbrooke's Hospital , Hills Road, Cambridge, CB2 2QQ, UK

    Anthony P. Cahn

  5. Kinderklinik der Universität, Würzburg, 97080 , Germany

    Volker Schuster

  6. Cattedra di Gen. Umana, Istituto di Scienze Biomediche Ospedale San Paolo, Milan, Italy

    Giovanni Porta & Paola Serafini

  7. Dip. di Patologia Umana ed Ereditaria, II Facolta' di Med., Univ. di Pavia, Italy

    Giovanni Porta

  8. Genetic Cancer Susceptibility Unit, International Agency for Research on Cancer, Lyon, France

    Luo Yin, Bakary Sylla & Giovanni Romeo

  9. Telethon Institute of Genetics and Medicine (TIGEM), San Raffaele Biomedical Science Park, Via Olgettina 58, Milan, 20132, Italy

    Massimo Zollo & Brunella Franco

  10. Lab Genetica Molecolare, Instituto Gaslini, Genoa, Italy

    Alessandra Bolino & Marco Seri

  11. Dept Microbiology and Pathology, University of Nebraska , Omaha, Nebraska, USA

    Arpad Lanyi, Jack R. Davis & Janos Sumegi

  12. Dept of Clinical Immunology, Royal Free Hospital School of Medicine, Pond Street, London, UK

    David Webster

  13. Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK

    Ann Harris

  14. Programme on Viral and Hereditary Factors in Carcinogenesis, International Agency for Research on Cancer, Lyon, France

    Gilbert Lenoir

  15. INSERM U429, Hopital des Enfants-Malades, Paris, 75015, France

    Genevieve de St Basile

  16. Great Ormond Street Hospital, London, WC1N 3JH, UK

    Alison Jones

  17. Haunersche Immundefektambulanz der LMU, Munich, 80336, Germany

    Bernd H. Behloradsky

Authors
  1. Alison J. Coffey

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  2. Robert A. Brooksbank

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  3. Oliver Brandau

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  4. Toshitaka Oohashi

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  5. Gareth R. Howell

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  6. Jacqueline M. Bye

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  8. Jillian Durham

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  9. Paul Heath

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  10. Paul Wray

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  11. Rebecca Pavitt

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  12. Jane Wilkinson

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  13. Margaret Leversha

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  14. Elizabeth Huckle

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  15. Charles J. Shaw-Smith

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  16. Andrew Dunham

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  17. Susan Rhodes

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  18. Volker Schuster

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  19. Giovanni Porta

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  20. Luo Yin

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  21. Paola Serafini

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  22. Bakary Sylla

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  23. Massimo Zollo

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  24. Brunella Franco

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  25. Alessandra Bolino

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  26. Marco Seri

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  27. Arpad Lanyi

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  28. Jack R. Davis

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  29. David Webster

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  30. Ann Harris

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  31. Gilbert Lenoir

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  32. Genevieve de St Basile

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  33. Alison Jones

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  34. Bernd H. Behloradsky

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  35. Helene Achatz

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  36. Jan Murken

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  37. Reinhard Fassler

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  38. Janos Sumegi

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  39. Giovanni Romeo

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  40. Mark Vaudin

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  41. Mark T. Ross

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  42. Alfons Meindl

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  43. David R. Bentley

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Corresponding authors

Correspondence toAlison J. Coffey orRobert A. Brooksbank.

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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 Genet20, 129–135 (1998). https://doi.org/10.1038/2424

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