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: 6162545
• 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/6162545
• 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 de-fects 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 sub-stantial proportion of cases. Detection of IL2RG mutations in SCID males allows: i) definition of X-linked SCID clinical features within the spectrum of all SCID; ii) study of specific muta-tions with regard to frequency and clinical severity; iii) study of functional characteristics of defective gamma chain protein encoded by mutated IL2RG from patinets with SCID; iv) participation in the evolving manage-ment of SCID families, including devising and performing carrier and prenatal testing; v) monitoring utilization of genetic services by X-linked SCID families; and vi) planning new therapeutic approaches. Research efforts have been aimed at mutation detection by single strand conformation polymorphism and dideoxy fingerprinting. A worldwide database of mutations has been set up. IL2RGbase, currently listing 150 independent mutations, two thirds of which were found in this laboratory. 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 achieved through collaboration with Alan Flake, MD. An affected male fetus was treated in utero with paternal CD34+ cells administered intraperitoneally at 17-20 wk of pregnancy. A term, healthy infant, with functional paternal lymphocytes, is now over 2 yr old. Ongoing genotype/phenotype correlation studies will show whether particular subsets of SCID patients are likely to benefit from retroviral gene therapy.

白介素2受体(IL2RG)的伽马链基因就是这种疾病 X连锁严重联合免疫缺陷(SCID)基因。这是 最常见的几种导致SCID综合征的基因缺陷， 每10,000到100,000名新生儿中就有1名发生。患有X连锁SCID的男性 通常死于持续性和机会性感染 除非通过骨髓移植挽救他们的生命。新的 突变在病例中所占的比例很小。检测 男性SCID患者IL2RG突变允许：I)X连锁SCID的定义 所有SCID的临床特征；ii)特异性研究 突变与频率和临床严重性的关系；iii)研究 人缺陷伽马链蛋白的功能特性研究 SCID患者IL2RG突变；iv)参与进化 SCID家族的管理，包括设计和实施携带者 和产前检测；五)监测遗传服务的利用情况 与X连锁的SCID家族；以及vi)规划新的治疗方法。 研究的目标是通过单链进行突变检测 构象多态和双脱氧指纹图谱。一个世界性的 已经建立了突变数据库。IL2RGbase，当前清单150 独立突变，其中三分之二是在这个实验室发现的。 独特的遗传特征，包括生殖系嵌合体，分支点A 发现了突变热点和5个突变热点。产前监护 高危妊娠的情况允许实施新生儿骨骼 骨髓移植，比典型的移植效果更好。 此外，还实现了一种新的、有前途的宫内移植。 通过与马里兰州艾伦·弗莱克的合作。一名受影响的男性胎儿 父亲CD34+细胞经腹膜腔内注射治疗宫内感染 怀孕17-20周。一个术语，健康的婴儿，有功能 父亲的淋巴细胞，现在已经超过2岁了。正在进行的基因型/表型 相关研究将显示SCID患者的特定亚群 很可能从逆转录病毒基因疗法中受益。