IL 2 RECEPTOR GAMMA CHAIN MUTATIONS IN SEVERE COMBINED IMMUNODEFICIENCY

严重联合免疫缺陷病中的 IL 2 受体伽马链突变

• 批准号: 2576524
• 负责人: J M PUCK
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2576524
• 关键词: bone marrow transplantation; cell transplantation; clinical research; cytokine receptors; embryo /fetus surgery; family genetics; gene mutation; gene therapy; genetic carriers; genetic disorder diagnosis; hematopoietic stem cells; human subject; human therapy evaluation; interleukin 2; prenatal diagnosis; severe combined immunodeficiency; sex linked trait; single strand conformation polymorphism

The gamma chain gene of the interleukin-2 receptor (IL2RG) is the disease gene for X-linked severe combined immunodeficiency (SCID). This is the most common of several gene defects causing the SCID syndrome, which occurs in 1 in 10,000 to 100,000 births. Males with X-linked SCID generally die of persistent and opportunistic infections in the first year of life unless they are rescued by bone marrow transplantation. New mutations account for a substantial proportion of cases. Detection of IL2RG mutations in SCID males allows: 1) definition of X-linked SCID clinical features within the spectrum of all SCID; ii) study of specific mutations with regard to frequency and clinical severity; iii) participation in the evolving management of SCID families, including devising and performing carrier and prenatal testing; iv) monitoring utilization of genetic services by X-linked SCID families; and v) planning new therapeutic approaches. Research efforts have been aimed at mutation detection by single strand conformation polymorphism and dideoxy fingerprinting, with 87 unrelated patient mutations detected to date. Unique genetic features including germ line mosaicism, a branch point A mutation and 5 mutation hot spots have been found. Prenatal monitoring of at-risk pregnancies has allowed for implementation of neonatal bone marrow transplantation, with improved results over typical transplants. Moreover, a new and promising in utero transplantation was made possible through collaboration with Alan Flake, MD, of Wayne State University Medical School. An affected male fetus was treated in utero with paternal CD34+ cells administered intraperitoneally at 17-20 week of pregnancy. A term, healthy infant, with functional paternal lymphocytes, is now over 1 year old. Ongoing genotype/phenotype correlation studies will show whether particular subsets of SCID patients are likely to benefit from retroviral gene therapy.

白细胞介素-2受体（IL-2 RG）的γ链基因是疾病 X连锁严重联合免疫缺陷（SCID）基因。这是 最常见的几种基因缺陷引起的SCID综合征， 发生率为1/10，000至100，000。X连锁SCID男性 通常死于持续性和机会性感染， 除非他们通过骨髓移植来挽救生命。新 突变占病例的很大比例。检测 SCID男性中的IL 2 RG突变允许：1）X连锁SCID的定义 所有SCID范围内的临床特征; ii）特异性SCID的研究 关于频率和临床严重性的突变; iii） 参与SCID家庭的不断发展的管理，包括 设计和执行携带者和产前检测; iv）监测 X连锁SCID家族对遗传服务的利用;以及v） 计划新的治疗方法。研究工作的目标是 单链构象多态性和双脱氧 指纹图谱，迄今为止检测到87个不相关的患者突变。 独特的遗传特征，包括生殖系嵌合，一个分支点A 发现5个突变热点。 的风险怀孕允许实施新生儿骨 骨髓移植，与典型的移植相比具有改善的结果。 此外，一种新的和有前途的子宫内移植成为可能 通过与韦恩州立大学的医学博士艾伦·弗莱克的合作 医学院一个受影响的男性胎儿在子宫内接受了父亲的治疗。 在妊娠17-20周腹膜内给予CD 34+细胞。 一个健康的足月婴儿，父亲的淋巴细胞功能正常，现在已经结束了。 1岁。正在进行的基因型/表型相关性研究将显示 SCID患者的特定亚群是否可能受益于 逆转录病毒基因疗法