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.

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，是一种广泛表达的对细胞内铁转运至关重要的受体。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，其特征是复发性肺感染、血小板减少症、无球蛋白血症、记忆性B细胞缺失、T细胞和B细胞激活缺陷以及体外巨核细胞生成受损。令人惊讶的是，尽管批评