{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T23:36:43Z","timestamp":1791329803477,"version":"4.3.1"},"reference-count":37,"publisher":"National Academy of Sciences","issue":"23","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1998,11,10]]},"abstract":"<jats:p>\n                    X-linked lymphoproliferative syndrome (XLP) is an inherited immunodeficiency characterized by increased susceptibility to Epstein\u2013Barr virus (EBV). In affected males, primary EBV infection leads to the uncontrolled proliferation of virus-containing B cells and reactive cytotoxic T cells, often culminating in the development of high-grade lymphoma. The\n                    <jats:italic>XLP<\/jats:italic>\n                    gene has been mapped to chromosome band Xq25 through linkage analysis and the discovery of patients harboring large constitutional genomic deletions. We describe here the presence of small deletions and intragenic mutations that specifically disrupt a gene named\n                    <jats:italic>DSHP<\/jats:italic>\n                    in 6 of 10 unrelated patients with XLP. This gene encodes a predicted protein of 128 amino acids composing a single SH2 domain with extensive homology to the SH2 domain of SHIP, an inositol polyphosphate 5-phosphatase that functions as a negative regulator of lymphocyte activation.\n                    <jats:italic>DSHP<\/jats:italic>\n                    is expressed in transformed T cell lines and is induced following\n                    <jats:italic>in vitro<\/jats:italic>\n                    activation of peripheral blood T lymphocytes. Expression of\n                    <jats:italic>DSHP<\/jats:italic>\n                    is restricted\n                    <jats:italic>in vivo<\/jats:italic>\n                    to lymphoid tissues, and RNA\n                    <jats:italic>in situ<\/jats:italic>\n                    hybridization demonstrates\n                    <jats:italic>DSHP<\/jats:italic>\n                    expression in activated T and B cell regions of reactive lymph nodes and in both T and B cell neoplasms. These observations confirm the identity of\n                    <jats:italic>DSHP<\/jats:italic>\n                    as the gene responsible for XLP, and suggest a role in the regulation of lymphocyte activation and proliferation. Induction of\n                    <jats:italic>DSHP<\/jats:italic>\n                    may sustain the immune response by interfering with\n                    <jats:italic>SHIP<\/jats:italic>\n                    -mediated inhibition of lymphocyte activation, while its inactivation in XLP patients results in a selective immunodeficiency to EBV.\n                  <\/jats:p>","DOI":"10.1073\/pnas.95.23.13765","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:35:50Z","timestamp":1027679750000},"page":"13765-13770","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":415,"title":["Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome"],"prefix":"10.1073","volume":"95","author":[{"given":"Kim E.","family":"Nichols","sequence":"first","affiliation":[{"name":"Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129; Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Memorial Sloan\u2013Kettering Cancer Center, New York, NY 10021; Axys Pharmaceuticals, San Diego, CA 92037; University of Texas, Southwestern Medical Center, Dallas, TX 75235; St. Jude Children\u2019s Research Hospital, Memphis, TN 38101; and Center for Cancer Research, Massachusetts Institute of Technology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. Paul","family":"Harkin","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129; Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Memorial Sloan\u2013Kettering Cancer Center, New York, NY 10021; Axys Pharmaceuticals, San Diego, CA 92037; University of Texas, Southwestern Medical Center, Dallas, TX 75235; St. Jude Children\u2019s Research Hospital, Memphis, TN 38101; and Center for Cancer Research, Massachusetts Institute of Technology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth","family":"Levitz","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129; Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Memorial Sloan\u2013Kettering Cancer Center, New York, NY 10021; Axys Pharmaceuticals, San Diego, CA 92037; University of Texas, Southwestern Medical Center, Dallas, TX 75235; St. Jude Children\u2019s Research Hospital, Memphis, TN 38101; and Center for Cancer Research, Massachusetts Institute of Technology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Krainer","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129; Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Memorial Sloan\u2013Kettering Cancer Center, New York, NY 10021; Axys Pharmaceuticals, San Diego, CA 92037; University of Texas, Southwestern Medical Center, Dallas, TX 75235; St. Jude Children\u2019s Research Hospital, Memphis, TN 38101; and Center for Cancer Research, Massachusetts Institute of Technology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn Ann","family":"Kolquist","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129; Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Memorial Sloan\u2013Kettering Cancer Center, New York, NY 10021; Axys Pharmaceuticals, San Diego, CA 92037; University of Texas, Southwestern Medical Center, Dallas, TX 75235; St. Jude Children\u2019s Research Hospital, Memphis, TN 38101; and Center for Cancer Research, Massachusetts Institute of Technology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameo","family":"Genovese","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129; Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Memorial Sloan\u2013Kettering Cancer Center, New York, NY 10021; Axys Pharmaceuticals, San Diego, CA 92037; University of Texas, Southwestern Medical Center, Dallas, TX 75235; St. Jude Children\u2019s Research Hospital, Memphis, TN 38101; and Center for Cancer Research, Massachusetts Institute of Technology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Bernard","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129; Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Memorial Sloan\u2013Kettering Cancer Center, New York, NY 10021; Axys Pharmaceuticals, San Diego, CA 92037; University of Texas, Southwestern Medical Center, Dallas, TX 75235; St. Jude Children\u2019s Research Hospital, Memphis, TN 38101; and Center for Cancer Research, Massachusetts Institute of Technology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Ferguson","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129; Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Memorial Sloan\u2013Kettering Cancer Center, New York, NY 10021; Axys Pharmaceuticals, San Diego, CA 92037; University of Texas, Southwestern Medical Center, Dallas, TX 75235; St. Jude Children\u2019s Research Hospital, Memphis, TN 38101; and Center for Cancer Research, Massachusetts Institute of Technology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Zuo","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129; Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Memorial Sloan\u2013Kettering Cancer Center, New York, NY 10021; Axys Pharmaceuticals, San Diego, CA 92037; University of Texas, Southwestern Medical Center, Dallas, TX 75235; St. Jude Children\u2019s Research Hospital, Memphis, TN 38101; and Center for Cancer Research, Massachusetts Institute of Technology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Snyder","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129; Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Memorial Sloan\u2013Kettering Cancer Center, New York, NY 10021; Axys Pharmaceuticals, San Diego, CA 92037; University of Texas, Southwestern Medical Center, Dallas, TX 75235; St. Jude Children\u2019s Research Hospital, Memphis, TN 38101; and Center for Cancer Research, Massachusetts Institute of Technology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan J.","family":"Buckler","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129; Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Memorial Sloan\u2013Kettering Cancer Center, New York, NY 10021; Axys Pharmaceuticals, San Diego, CA 92037; University of Texas, Southwestern Medical Center, Dallas, TX 75235; St. Jude Children\u2019s Research Hospital, Memphis, TN 38101; and Center for Cancer Research, Massachusetts Institute of Technology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Wise","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129; Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Memorial Sloan\u2013Kettering Cancer Center, New York, NY 10021; Axys Pharmaceuticals, San Diego, CA 92037; University of Texas, Southwestern Medical Center, Dallas, TX 75235; St. Jude Children\u2019s Research Hospital, Memphis, TN 38101; and Center for Cancer Research, Massachusetts Institute of Technology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Ashley","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129; Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Memorial Sloan\u2013Kettering Cancer Center, New York, NY 10021; Axys Pharmaceuticals, San Diego, CA 92037; University of Texas, Southwestern Medical Center, Dallas, TX 75235; St. Jude Children\u2019s Research Hospital, Memphis, TN 38101; and Center for Cancer Research, Massachusetts Institute of Technology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Lovett","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129; Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Memorial Sloan\u2013Kettering Cancer Center, New York, NY 10021; Axys Pharmaceuticals, San Diego, CA 92037; University of Texas, Southwestern Medical Center, Dallas, TX 75235; St. Jude Children\u2019s Research Hospital, Memphis, TN 38101; and Center for Cancer Research, Massachusetts Institute of Technology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus B.","family":"Valentine","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129; Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Memorial Sloan\u2013Kettering Cancer Center, New York, NY 10021; Axys Pharmaceuticals, San Diego, CA 92037; University of Texas, Southwestern Medical Center, Dallas, TX 75235; St. Jude Children\u2019s Research Hospital, Memphis, TN 38101; and Center for Cancer Research, Massachusetts Institute of Technology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Thomas","family":"Look","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129; Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Memorial Sloan\u2013Kettering Cancer Center, New York, NY 10021; Axys Pharmaceuticals, San Diego, CA 92037; University of Texas, Southwestern Medical Center, Dallas, TX 75235; St. Jude Children\u2019s Research Hospital, Memphis, TN 38101; and Center for Cancer Research, Massachusetts Institute of Technology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Gerald","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129; Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Memorial Sloan\u2013Kettering Cancer Center, New York, NY 10021; Axys Pharmaceuticals, San Diego, CA 92037; University of Texas, Southwestern Medical Center, Dallas, TX 75235; St. Jude Children\u2019s Research Hospital, Memphis, TN 38101; and Center for Cancer Research, Massachusetts Institute of Technology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David E.","family":"Housman","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129; Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Memorial Sloan\u2013Kettering Cancer Center, New York, NY 10021; Axys Pharmaceuticals, San Diego, CA 92037; University of Texas, Southwestern Medical Center, Dallas, TX 75235; St. Jude Children\u2019s Research Hospital, Memphis, TN 38101; and Center for Cancer Research, Massachusetts Institute of Technology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel A.","family":"Haber","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129; Division of Pediatric Oncology, Dana\u2013Farber Cancer Institute, Boston, MA 02115; Department of Pathology, Memorial Sloan\u2013Kettering Cancer Center, New York, NY 10021; Axys Pharmaceuticals, San Diego, CA 92037; University of Texas, Southwestern Medical Center, Dallas, TX 75235; St. Jude Children\u2019s Research Hospital, Memphis, TN 38101; and Center for Cancer Research, Massachusetts Institute of Technology,..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1998,11,10]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-118-1-199301010-00009"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0896-906"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197911223012101"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198102193040804"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.72.4.1622"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90513-8"},{"key":"e_1_3_3_7_2","first-page":"5","volume":"67","author":"Purtilo D","year":"1992","unstructured":"D Purtilo, R Strobach, M Okano, J Davis Lab Invest 67, 5\u201323 (1992).","journal-title":"Lab Invest"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(75)92004-8"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320400309"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-106-4-538"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-199510000-00001"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19870415)59:8<1419::AID-CNCR2820590807>3.0.CO;2-P"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.3109\/15513819109065466"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.84.7.2015"},{"key":"e_1_3_3_15_2","first-page":"349","volume":"82","author":"Skare J","year":"1989","unstructured":"J Skare, J Sullivan, A Milunsky Hum Genet 82, 349\u2013353 (1989).","journal-title":"Hum Genet"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0165-4608(90)90026-7"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320330331"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1993.1169"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1993.1298"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1159\/000472230"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.9.4005"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0194-98"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/361751a0"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.21.9628"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.10.9.1084"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/383263a0"},{"key":"e_1_3_3_27_2","doi-asserted-by":"crossref","first-page":"2234","DOI":"10.4049\/jimmunol.157.6.2234","volume":"157","author":"Chacko G","year":"1996","unstructured":"G Chacko, S Tridandapani, J Damen, L Liu, G Krystal, K Coggeshall J Immunol 157, 2234\u20132238 (1996).","journal-title":"J Immunol"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V88.8.2833.bloodjournal8882833"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2400559"},{"key":"e_1_3_3_30_2","doi-asserted-by":"crossref","first-page":"2536","DOI":"10.4049\/jimmunol.129.6.2536","volume":"129","author":"Lindsten T","year":"1982","unstructured":"T Lindsten, J Seeley, M Ballow, K Sakamoto, S S Onge, J Yetz, P Aman, D Purtilo J Immunol 129, 2536\u20132540 (1982).","journal-title":"J Immunol"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/0090-1229(90)90133-B"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80337-2"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.17.8.4305"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(02)00511-0"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V89.8.2745"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1042\/bst0240994"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.16.10396"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.95.23.13765","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,22]],"date-time":"2023-04-22T08:14:23Z","timestamp":1682151263000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.95.23.13765"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1998,11,10]]},"references-count":37,"journal-issue":{"issue":"23","published-print":{"date-parts":[[1998,11,10]]}},"alternative-id":["10.1073\/pnas.95.23.13765"],"URL":"https:\/\/doi.org\/10.1073\/pnas.95.23.13765","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[1998,11,10]]},"assertion":[{"value":"1998-08-31","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"1998-11-10","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}