Novel Immunodeficiency caused by TFRC Mutation

TFRC 突变引起的新型免疫缺陷

基本信息

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
项目类别：
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

项目摘要

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）：铁是许多基本细胞过程所必需的，包括红细胞和淋巴细胞发育和功能。由TFRC编码的转铁蛋白受体1（TFR1）是一种对细胞内铁转运至关重要的广泛表达的受体。 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.令人惊讶的是，尽管关键 TFR1介导的铁转运在红细胞生成中，患者几乎没有微细胞贫血。近亲科威特家族的所有14个受影响的成员都是纯合的TFRC中的错义突变，该突变在TFR1内部化信号基序中代替酪氨酸残基20ytrf23与组氨酸（Y20H）。与来自健康个体的静息淋巴细胞相比，这些淋巴细胞表达最少的表面TFR1，患者的静止淋巴细胞表达了很高的表面TFR1。来自患者的成纤维细胞还表现出表面TFR1表达增加，并且具有缺陷的转铁蛋白摄取，表明Y20H突变会损害TFR1内吞作用，而TFR1依赖性依赖于铁的全脱旋素进口蛋白。患者的成红细胞的TFR1表面表达仅略有增加，这表明在红斑谱系中选择性表达的蛋白质可以补偿Y20H突变对该谱系中TFR1内在化的影响。潜在的候选者是屈服者STEAP3，它在红细胞细胞中选择性表达，与TFR1共定位，并具有288YQRF291内部化信号基序。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TFR1内吞作用，受体配体内在化和铁转运。我们提出，野生型（WT）TFRC的可渗透性铁螯合物和/或表达纠正患者淋巴细胞功能和巨核细胞分化的缺陷。最后，我们将检验以下假设：STEAP3与TFR1相关，从而促进其内在化和铁的转运，从而从患者中TFR1突变的影响中避免了红细胞谱系。 TFRC缺乏症的分子基础和发病机理的鉴定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的早期诊断，以增加TFR1表面表达增加，早期干预血肿干细胞移植（HSCT）（HSCT）（HSCT）以及遗传咨询。提出的对突变的研究将适用于与TFR1缺乏症相似的表型的PID。