GENETIC ASPECTS OF IMMUNODEFICIENCIES

免疫缺陷的遗传方面

• 批准号: 6349782
• 负责人: MARY ELLEN CONLEY
• 金额: $ 27.99万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6349782
• 关键词: B cell receptor; B lymphocyte; cell differentiation; clinical research; gene mutation; genetic polymorphism; human genetic material tag; human subject; hypogammaglobulinemia; immunogenetics; immunoglobulin genes; molecular pathology; protein tyrosine kinase; tissue /cell culture; transfection

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.

描述（改编自研究者摘要）：总体目标 该项目旨在确定B细胞严重缺陷的遗传基础， 发展 大多数早期发病的患者 低丙种球蛋白血症（XLA），细胞质酪氨酸突变 激酶，Btk. B细胞缺陷的严重程度存在变异性， 这些患者，甚至在Btk中具有无效突变的患者中。这 表明还有其他遗传或环境因素 影响疾病的严重程度。 调查人员最近表示， B细胞发育的严重缺陷也可能是由于基因突变 编码B细胞抗原受体复合物（BRC）的组分，或 前BCR包括：μ重链;替代轻链，λ-5;或 免疫球蛋白相关蛋白，IG α。 几种多晶 这些基因中的变体也已被鉴定。 具体目标为 下一个计划期为： 继续确定和描述 Btk中的突变可能性，多态性变体的组成部分， 前BCR和BCR影响患者B细胞缺陷的严重程度 将对XLA进行检查。 2. 评估功能性后果 在B细胞和前B细胞组分中鉴定的突变 抗原受体复合物 在COS细胞中使用表达载体， 研究人员将确定最近发现的突变是否 λ-5、IG α或μ重链，导致蛋白质稳定性降低， 未能与BCR的其他组分相互作用，或如果它们抑制 信号转导 3. 识别和表征相关突变 用于非典型疾病患者的B细胞发育缺陷。 的 免疫缺陷患者中缺陷基因的鉴定已经 对受影响患者的潜在护理的临床意义。 此外，本发明还提供了一种方法， 免疫缺陷与井中特定突变的关联 所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