Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome
Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome
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DOI：
10.1073/pnas.95.23.13765
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发表时间：
1998-11-10
影响因子：
11.1
通讯作者：
Haber, DA
中科院分区：
文献类型：
--
作者：
Nichols, KE;Harkin, DP;Haber, DA
x连锁淋巴细胞增生性综合征（XLP）是一种遗传性免疫缺陷，其特征是对eb病毒（EBV）易感性增加。在受感染的男性中，原发性EBV感染导致含病毒的B细胞和反应性细胞毒性T细胞不受控制的增殖，通常最终发展为高级别淋巴瘤。通过连锁分析和发现患者存在较大的体质基因组缺失，XLP基因被定位到染色体带Xq25。我们在这里描述了在10个不相关的SLP患者中的6个中存在的小缺失和基因内突变，这些突变特异性地破坏了一个名为DSHP的基因，该基因编码一个由128个氨基酸组成的预测蛋白，该蛋白组成一个单一的SH2结构域，与SHIP的SH2结构域具有广泛的同源性，SHIP是一种肌醇多磷酸5磷酸酶，作为淋巴细胞激活的负调节因子。DSHP在转化的T细胞系中表达，并在体外激活外周血T淋巴细胞后被诱导。DSHP在体内的表达仅限于淋巴组织，RNA原位杂交显示DSHP在反应性淋巴结的活化T细胞区和B细胞区以及T细胞和B细胞肿瘤中均有表达。这些观察结果证实了DSHP是导致XLP的基因，并提示其在淋巴细胞活化和增殖的调节中起作用。诱导DSHP可能通过干扰ship介导的淋巴细胞活化抑制来维持免疫应答，而XLP患者的DSHP失活导致对EBV的选择性免疫缺陷。
x-linked lymphoproliferative syndrome (XLP) is an inherited immunodeficiency characterized by increased susceptibility to Epstein-Barr 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 XLP 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 DSHP in 6 of 10 unrelated patients with SLP, 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 poly phosphate 5-phosphatase that functions as a negative regulator of lymphocyte activation. DSHP is expressed in transformed T cell lines and is induced following in vitro activation of peripheral blood T lymphocytes. Expression of DSHP is restricted in vivo to lymphoid tissues, and RNA in situ hybridization demonstrates DSHP 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 DSHP as the gene responsible for XLP, and suggest a role in the regulation of lymphocyte activation and proliferation. Induction of DSHP may sustain the immune response by interfering with SHIP-mediated inhibition of lymphocyte activation, while its inactivation in XLP patients results in a selective immunodeficiency to EBV.