IDENTIFICATION OF THE XLP GENE

X连锁淋巴增生性疾病是一种遗传性疾病 以易感性增加为特征的免疫缺陷综合征 Epstein-Barr病毒(EBV)感染。而不是短暂的传染性 初次暴露于EBV后的单核细胞增多症，40%-50%的XLP男孩 经历致命的不受控制的淋巴增殖和20%-30%的发展 EB病毒相关淋巴瘤。因此，XLP代表了一种遗传模型 EBV相关淋巴组织增殖及相关机制的研究 肿瘤发生学。XLP也与EBV相关的临床相关 HIV感染或免疫抑制患者中出现的淋巴瘤 骨髓或实体器官移植后。这样做的目的是 该项目是为了鉴定和鉴定XLP的基因。通过RFLP 分析表明，XLP与Xq25基因座有关联，到目前为止，有3个与Xq25基因无关 据报道，有患者分享了该基因座的细胞遗传学缺失。 为了确定受影响的基因，定位克隆策略将是 涉及以下几种方法：(1)筛选阵列式YAC 在XLP基因座上具有已知和新的遗传标记的文库 生成跨越XLP缺失的YAC的线性重叠群，(2)到 识别这些YAC中包含的编码序列，方法是生成 从YAC DNA中提取粘粒文库，然后通过 外显子扩增技术，或通过这一过程克隆cdna 直接选择；(3)通过以下方式对成绩单进行表征 评估与其他已知基因的同源性，表达模式 组织和物种之间的保守性，并确认 转录本是通过执行突变分析而涉及的基因 患者样本，(4)评价XLP基因产物的性质 通过亚细胞定位的检查，对细胞生长的影响 和增殖，与其他蛋白质的结合，以及产生 可能的动物模型。克隆XLP基因将提供更好的 对EBV诱发淋巴瘤和非霍奇金淋巴瘤机制的认识 宿主通过它识别EBV感染的细胞并对其做出反应。 鉴定XLP基因产物的性质可能提供线索 这些疾病和其他相关人类疾病的治疗策略 带着EB病毒。

X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency syndrome characterized by increased susceptibility to Epstein-Barr virus (EBV) infection. Rather than transient infectious mononucleosis after primary exposure to EBV, 40-50% of boys with XLP experience fatal uncontrolled lymphoproliferation and 20-30% develop EBV-associated lymphoma. As such, XLP represents a genetic model to study mechanisms involved in EBV-associated lymphoproliferation and tumorigenesis. XLP also has clinical relevance to EBV-associated lymphomas seen in patients with HIV infection or those immunosuppressed after bone marrow or solid organ transplantation. The goal of this project is to identify and characterize the gene for XLP. Through RFLP analysis, XLP has been linked to the locus Xq25 and to date, 3 unrelated patients have been reported sharing cytogenetic deletions at this locus. To determine the affected gene, a positional cloning strategy will be used involving the following approaches: (1) To screen arrayed YAC libraries with known and novel genetic markers at the XLP locus and to generate a linear contig of YACs spanning the XLP deletion, (2) To identify coding sequences contained within these YACs by generating a cosmid library from YAC DNA and then either identifying exons through the "exon amplification" technique, or cDNA clones through the process of "direct selection", (3) To characterize transcripts through evaluation of homology to other known genes, pattern of expression among tissues and conservation between species, and to confirm that identified transcripts are the involved gene by performing mutational analysis of patient samples, (4) To evaluate properties of the XLP gene product through examination of subcellular localization, effects on cell growth and proliferation, association with other proteins, and generation of possible animal models. Cloning the XLP gene will provide a better understanding of the mechanisms through which EBV induces lymphoma and through which the host recognizes and responds to EBV-infected cells. Characterizing properties of the XLP gene product may provide clues to therapeutic strategies for these and other human diseases associated with EBV.