MUTATIONS OF PROGRAMMED CELL DEATH GENE FAS

程序性细胞死亡基因 FAS 的突变

• 批准号: 6162553
• 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/6162553
• 关键词: T lymphocyte; apoptosis; autoimmune disorder; cell population study; clinical research; family genetics; gene expression; genetic disorder; genetically modified animals; human genetic material tag; human subject; immune tolerance /unresponsiveness; immunoregulation; laboratory mouse; leukocyte activation disorder; lymphocyte proliferation; oncogenes

Thirty-three unrelated children and their families have been studied with a rare autoimmune lymphoproliferative syndrome (ALPS) characterized by massive non-malignant lymphadenopathy, autoim-mune phenomena and expanded populations of TCR/CD3+, CD4-, CD8- lymphocytes. These findings are due to a genetic defect in the ability of T lymphocytes to respond to normal immunoregulatory mechanisms, in turn caused by defects of lymphocyte apoptosis. Fifteen children were found to have defective Fas-mediated T lymphocyte apoptosis, and in 13 of these children a unique, deleterious mutation was found in the Fas gene. The heterozygous mutations produce defective protein with a dominant negative effect on apoptosis when they are co-expressed with normal Fas. The occurrence of Fas mutations together with abnormal T cell apoptosis in ALPS patients indicates an involvement of Fas in this newly recognized disorder. Family studies demonstrate that the inheritance of the mutant Fas alleles causes a dominantly inherited cellular apoptosis defect. However, overt autoimmunity appears to require additional factors besides heterozygous Fas mutation. Further studies of family members revealed multiple extended families in which a dominant negative Fas mutation segregated with clinical abnormalities ranging from benign lymphadenopathy to autoimmune disease with elevated double negative T cells to Hodgkin!s disease and non-Hodgkin's lymphoma. The possibility that Fas and other proteins which participate in lymphocyte apoptosis might function as oncogenes in the development of Hodgkin's disease is being pursued. In addition a transgenic mouse model of dominant negative Fas mutations is being developed. Constructs placing mutant Fas alleles under the control of the actin promoter have been used to generate transgenic mice in which expression studies are being undertaken.

33名无血缘关系的儿童和他们的家庭进行了研究， 一种罕见的自身免疫性淋巴组织增生综合征（ALPS），其特征是 巨大的非恶性淋巴结病，自身免疫现象和扩大 TCR/CD 3+、CD 4-、CD 8-淋巴细胞群。这些发现是由于 T淋巴细胞对正常免疫反应能力的遗传缺陷 免疫调节机制，又由淋巴细胞缺陷引起 凋亡15名儿童被发现有缺陷的Fas介导的T细胞 淋巴细胞凋亡，并在这些儿童中的13个独特的，有害的 Fas基因突变。杂合突变产生 缺陷蛋白，当它们与细胞凋亡相关时， 与正常Fas共表达。Fas突变的发生 与ALPS患者中异常T细胞凋亡一起表明， Fas参与这种新认识的疾病。家庭研究 表明突变Fas等位基因的遗传导致了 显性遗传性细胞凋亡缺陷。然而，公开 除了杂合子外，自身免疫似乎还需要其他因素 Fas突变。对家庭成员的进一步研究显示， 显性负性Fas突变分离的大家族 临床异常从良性淋巴结病到 自身免疫性疾病，双阴性T细胞升高到霍奇金淋巴瘤！S 疾病和非霍奇金淋巴瘤。Fas和其他 参与淋巴细胞凋亡的蛋白质可能作为 癌基因在何杰金氏病发展中的作用正在研究中。在 此外，显性负性Fas突变的转基因小鼠模型， 正在开发中。将突变Fas等位基因置于对照下的构建体 的肌动蛋白启动子已被用于产生转基因小鼠，其中 正在进行表达研究。