GENETIC ASPECTS OF IMMUNODEFICIENCIES

说明(改编自调查员摘要)：的总体目标 这个项目是为了确定B细胞严重缺陷的遗传基础 发展。大多数早发患者 胞浆酪氨酸突变的低丙种球蛋白血症(XLA) 激酶，BTK。在B细胞缺陷的严重程度上存在差异 这些患者，即使在BTK零突变的患者中也是如此。这 表明还有其他遗传或环境因素 影响疾病的严重程度。调查人员最近表明， B细胞发育的严重缺陷也可能是由于基因突变造成的 编码B细胞抗原受体复合体(BRC)或 前bcr包括：MU重链；替代轻链，lambda-5；或 免疫球蛋白相关蛋白，Igα。几个多态 这些基因中的变异也已被识别出来。具体目标是 下一个项目阶段是：1.继续确定和描述 BTK基因突变。组件的多态变体的可能性 BCR前和BCR对B细胞缺陷严重程度的影响 将对XLA进行检查。2.评估以下各项的功能后果 B细胞和前B细胞成分中发现的突变 抗原受体复合体。利用COS细胞中的表达载体， 调查人员将确定最近发现的突变是否 Lambda-5、Igα或Mu重链，导致蛋白质稳定性降低， 未能与BCR的其他组件相互作用或如果它们抑制 信号转导。3.识别和描述相关突变 用于非典型疾病患者的B细胞发育缺陷。这个 免疫缺陷患者中缺陷基因的鉴定 对受影响患者的潜在护理的临床意义。此外, 免疫缺陷与井中特定突变的关系 已描述的基因有助于阐明该基因在正常B细胞中的功能 发展。

DESCRIPTION (Adapted from the Investigator's abstract): The overall goal of this project is to determine the genetic basis of profound defects in B-cell development. The majority of patients with early onset hypoagammaglobulinemia (XLA) who have mutations in the cytoplasmic tyrosine kinase, Btk. There is variability in the severity of the B-cell defect in these patients, even among patients who have null mutations in Btk. This suggests that there are other genetic or environmental factors that influence the severity of disease. The investigator has recently shown that severe defects in B-cell development may also be due to mutations in genes that encode components of the B-cell antigen receptor complex (BRC) or pre-BCR including: mu heavy chains; the surrogate light chain, lambda-5; or the immunoglobulin associated protein, Ig alpha. Several polymorphic variants in these genes have also been identified. The specific aims for the next project period are: 1. Continue to identify and characterize mutations in Btk. The possibility that polymorphic variants of components of the pre-BCR and BCR affect the severity of the B-cell defect in patients with XLA will be examined. 2. Evaluate the functional consequences of mutations identified in the components of the B-cells and the pre-B-cell antigen receptor complex. Using expression vectors in COS cells, the investigator will determine whether the recently identified mutations in lambda-5, Ig alpha or mu heavy chain, result in decreased protein stability, failure to interact with other components of the BCR or if they inhibit signal transduction. 3. Identify and characterize mutations responsible for defects in B-cell development in patients with atypical disease. The identification of the defective genes in patients with immunodeficiency has clinical implications for potential care of affected patients. In addition, the association of immunodeficiency with particular mutations in a well described gene helps elucidate the function of that gene in normal B-cell development.