Novel Immunodeficiency caused by TFRC Mutation

TFRC 突变引起的新型免疫缺陷

• 批准号: 8564631
• 负责人: RAIF SALIM GEHA
• 金额: $ 24.53万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8564631
• 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.

描述（由申请人提供）：铁对于许多基本细胞过程是必需的，包括红细胞和淋巴细胞的发育和功能。转铁蛋白受体 1 (TfR1) 由 TFRC 编码，是一种广泛表达的受体，对细胞内铁转运至关重要。利用全基因组测序 (WGS)，我们在一种新型原发性免疫缺陷 (PID) 中发现了第一个人类 TFRC 突变，其特征是反复鼻窦肺部感染、血小板减少、丙种球蛋白血症、记忆 B 细胞缺失、T 和 B 细胞活化缺陷以及体外巨核细胞生成受损。令人惊讶的是，尽管受到批评 由于TfR1介导的铁转运在红细胞生成中的作用，患者很少或没有小细胞性贫血。 科威特近亲家族的所有 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)。与健康个体的静息淋巴细胞表达极少量的表面 TfR1 相比，来自患者的静息淋巴细胞表达非常高水平的表面 TfR1。患者的成纤维细胞还表现出表面 TfR1 表达增加，并且转铁蛋白摄取有缺陷，表明 Y20H 突变损害了 TfR1 内吞作用和 TfR1 依赖的含铁全转铁蛋白的细胞内输入。患者成红细胞上的 TfR1 表面表达仅略有增加，表明在红细胞谱系中选择性表达的蛋白质可能补偿 Y20H 突变对该谱系中 TfR1 内化的影响。一个潜在的候选者是铁还原酶 Steap3，它在红细胞中选择性表达，与 TfR1 共定位，并具有 288YQRF291 内化信号基序。 我们将检验以下假设：TFRC 中的 Y20H 突变会损害患者淋巴细胞中的 TfR1 内吞作用、受体-配体内化和铁转运。我们建议细胞可渗透的铁螯合物和/或野生型（WT）TFRC的表达可以纠正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 Steap3 与 TfR1 相关的假设，从而促进其内化和铁转运，从而使红细胞谱系免受患者 TfR1 突变的影响。 识别 TFRC 缺陷的分子基础和发病机制具有重要的预后和治疗意义，包括通过流式细胞仪分析脐带血淋巴细胞 TfR1 表面表达增加进行早期诊断、造血干细胞移植 (HSCT) 的早期干预以及遗传咨询。拟议的突变研究将适用于表型与 TfR1 缺陷相似的 PID。