Novel Immunodeficiency caused by TFRC Mutation

TFRC 突变引起的新型免疫缺陷

• 批准号: 8726281
• 负责人: RAIF SALIM GEHA
• 金额: $ 21.75万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8726281
• 关键词: Affect; Agammaglobulinemia; B-Cell Activation; Binding; Blood Platelets; Bone Marrow Cells; CD34 gene; Cell Lineage; Cell physiology; Cells; Complex; Defect; Development; Disease; Early Diagnosis; Early Intervention; Endocytosis; Erythroblasts; Erythrocytes; Erythroid; Erythroid Cells; Erythropoiesis; Exhibits; Family; Fibroblasts; Generations; Genetic Counseling; Hematopoietic Stem Cell Transplantation; Histidine; Human; Immunologic Deficiency Syndromes; In Transferrin; In Vitro; Individual; Infection; Intracellular Transport; Iron; Iron Chelating Agents; Iron Compounds; Ligands; Lymphocyte; Lymphocyte Function; Mediating; Megakaryocytes; Memory B-Lymphocyte; Missense Mutation; Molecular; Mutate; Mutation; Organic Iron Compounds; Pathogenesis; Patients; Phenotype; Platelet Count measurement; Positioning Attribute; Proteins; Recurrence; Rest; Role; Serum Proteins; Signal Transduction; Surface; T-Lymphocyte; TFRC gene; Testing; Therapeutic; Thrombocytopenia; Transferrin; Tyrosine; Umbilical Cord Blood; Vaccines; base; congenital immunodeficiency; ferric ammonium citrate; genome sequencing; holotransferrin; human TFRC protein; iron (III) reductase; member; microcytic anemia; novel; prognostic; public health relevance; receptor; selective expression; uptake

DESCRIPTION (provided by applicant): Iron is necessary for many fundamental cellular processes, including erythrocyte and lymphocyte development and function. Transferrin receptor 1 (TfR1), encoded by TFRC, is a widely expressed receptor critical for intracellular iron transport. Using whole genome sequencing (WGS), we have identified the first human mutation in TFRC in a novel primary immunodeficiency (PID) characterized by recurrent sinopulmonary infections, thrombocytopenia, agammaglobulinemia, absent memory B cells, defective T and B cell activation, and impaired megakaryocyte generation in vitro. Surprisingly, despite the critical role of TfR1-mediated iron transport in erythropoiesis, the patients had little or no microcytic anemia. All 14 affected members of a consanguineous Kuwaiti family were homozygous for a missense mutation in TFRC, which substitutes the tyrosine residue in the TfR1 internalization signal motif 20YTRF23 with histidine (Y20H). In contrast to resting lymphocytes from healthy individuals, which express minimal amounts of surface TfR1, resting lymphocytes from the patients express very high levels of surface TfR1. Fibroblasts from the patients also exhibit increased surface TfR1 expression and have defective transferrin uptake, indicating that the Y20H mutation impairs TfR1 endocytosis and TfR1-dependent intracellular import of iron-laden holotransferrin. TfR1 surface expression on the patients' erythroblasts was only slightly increased, suggesting that a protein expressed selectively in the erythroid lineage may compensate for the effect of the Y20H mutation on TfR1 internalization in that lineage. A potential candidate is the ferrireductase Steap3, which is selectively expressed in erythroid cells, co-localizes with TfR1, and has a 288YQRF291 internalization signal motif. We will test the hypothesis that the Y20H mutation in TFRC impairs TfR1 endocytosis, receptor-ligand internalization, and iron transport in the patients' lymphocytes. We propose that cell permeable iron chelates and/or expression of wild type (WT) TFRC correct the defects in lymphocyte function and megakaryocyte differentiation in the patients. Finally, we will test the hypothesis that Steap3 associates with TfR1, thereby promoting its internalization and iron transport, thus sparing the red cell lineage from the effects of the TfR1 mutation in the patients. Identificationof the molecular basis and pathogenesis of TFRC deficiency has important prognostic and therapeutic implications, including early diagnosis by flow cytometric analysis of cord blood lymphocytes for increased TfR1 surface expression, early intervention with hematopoietic stem cell transplantation (HSCT), and genetic counseling. The proposed studies of the mutation will be applicable to PIDs with a phenotype similar to that of TfR1 deficiency.

说明(申请人提供)：铁是许多基本的细胞过程所必需的，包括红细胞和淋巴细胞的发育和功能。转铁蛋白受体1(TfR1)是由转铁蛋白受体1(TFRC)编码的一种广泛表达的受体，与细胞内铁转运有关。利用全基因组测序(WGS)，我们在一种新型的原发免疫缺陷(PID)中发现了第一个人类TFRC突变，其特征是反复的鼻肺感染、血小板减少、无丙种球蛋白血症、记忆B细胞缺失、T和B细胞激活缺陷以及体外巨核细胞生成障碍。令人惊讶的是，尽管关键 TfR1介导的铁转运在红细胞生成中的作用患者很少或根本没有小细胞性贫血。一个科威特血亲家庭的14名受影响成员都是TFRC错义突变的纯合子，该突变将TfR1内化信号基序20YTRF23中的酪氨酸残基替换为组氨酸(Y20H)。与健康人的静止淋巴细胞表达极少量的表面TfR1不同，患者的静止淋巴细胞表达非常高水平的表面TfR1。患者成纤维细胞表面TfR1表达增加，转铁蛋白摄取有缺陷，表明Y20H突变损害了TfR1内吞作用和TfR1依赖的铁载全转铁蛋白的细胞内输入。患者红细胞表面TfR1的表达仅略有增加，提示在红系中选择性表达的蛋白质可能补偿了Y20H突变对该系中TfR1内化的影响。一个潜在的候选基因是铁还原酶Steap3，它选择性地在红系细胞中表达，与TfR1共定位，具有288YQRF291内化信号基序。我们将验证这样的假设，即TFRC中的Y20H突变损害了TfR1的内吞作用、受体-配体内化和患者淋巴细胞中的铁运输。我们认为细胞通透性铁络合物和/或表达野生型(WT)TFRC纠正了患者淋巴细胞功能和巨核细胞分化的缺陷。最后，我们将检验这一假设，即Steap3与TfR1相关联，从而促进其内化和铁的运输，从而使患者的红细胞谱系免受TfR1突变的影响。明确TFRC缺乏症的分子基础和发病机制具有重要的预后和治疗意义，包括通过流式细胞术分析脐血淋巴细胞表面TfR1表达增加的早期诊断，早期造血干细胞移植(HSCT)的干预，以及遗传咨询。建议的突变研究将适用于表型类似于TfR1缺乏症的PIDs。