MUTATIONS OF PROGRAMMED CELL DEATH GENE FAS

程序性细胞死亡基因 FAS 的突变

• 批准号: 5203424
• 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/5203424
• 关键词: T lymphocyte; alleles; apoptosis; cell population study; child (0-11); cytogenetics; family genetics; gene expression; gene mutation; human genetic material tag; human subject; human tissue; immunoregulation; lymphocyte proliferation; oncogenes; phenotype

Five unrelated children have been described with a rare autoimmune lymphoproliferative syndrome (ALPS) characterized by massive non-malignant lymphadenopathy, autoimmune phenomena and expanded populations of TCR/CD3+, CD4-, CD8- lymphocytes. These findings, suggesting a genetic defect in the ability of T lymphocytes to respond to normal immunoregulatory mechanisms, prompted an evaluation of lymphocyte apoptosis. Each child was found to have defective Fas-mediated T lymphocyte apoptosis associated with a unique, deleterious Fas gene mutation. One mutation appeared to cause a simple loss of function; however, four others had a dominant negative phenotype when co-expressed with normal Fas. Family studies demonstrated the inheritance of the mutant Fas alleles. The occurrence of Fas mutations together with abnormal T cell apoptosis in ALPS patients suggests an involvement of Fas in this newly recognized disorder of lymphocyte homeostasis and peripheral self-tolerance. Further studies of family members revealed one extended family 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, diagnosed in 2 individuals after several years of benign adenopathy. 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.

五个无关的儿童被描述患有罕见的自身免疫性疾病 淋巴组织增生综合征 (ALPS) 的特征是大量 非恶性淋巴结病、自身免疫现象和扩大 TCR/CD3+、CD4-、CD8- 淋巴细胞群。 这些发现， 提示 T 淋巴细胞反应能力存在遗传缺陷 正常的免疫调节机制，促使对 淋巴细胞凋亡。 每个孩子都被发现有缺陷 Fas 介导的 T 淋巴细胞凋亡与一种独特的、有害的 Fas基因突变。 一种突变似乎导致了简单的缺失 功能;然而，另外四个人在 与正常Fas共表达。 家庭研究表明 突变 Fas 等位基因的遗传。 Fas突变的发生 与 ALPS 患者中异常的 T 细胞凋亡一起表明 Fas 与这种新发现的淋巴细胞疾病有关 体内平衡和外周自我耐受性。 进一步研究家庭 成员们透露了一个大家庭，其中存在显性负性 Fas 突变与临床异常（从良性到良性）分离 淋巴结肿大与双阴性 T 升高的自身免疫性疾病 经多次检查后，2 人被诊断出患有霍奇金病的细胞 多年的良性腺病。 Fas 和其他蛋白质的可能性 参与淋巴细胞凋亡的基因可能作为癌基因 正在追踪霍奇金病的发展。