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


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.

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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.

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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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Correspondence to Alison J. Coffey or Robert 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 Genet 20, 129–135 (1998).

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