A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency

• Published in: Nature genetics Vol. 48; no. 1; pp. 74 - 78
• Main Authors: Jabara, Haifa H, Boyden, Steven E, Chou, Janet, Ramesh, Narayanaswamy, Massaad, Michel J, Benson, Halli, Bainter, Wayne, Fraulino, David, Rahimov, Fedik, Sieff, Colin, Liu, Zhi-Jian, Alshemmari, Salem H, Al-Ramadi, Basel K, Al-Dhekri, Hasan, Arnaout, Rand, Abu-Shukair, Mohammad, Vatsayan, Anant, Silver, Eli, Ahuja, Sanjay, Davies, E Graham, Sola-Visner, Martha, Ohsumi, Toshiro K, Andrews, Nancy C, Notarangelo, Luigi D, Fleming, Mark D, Al-Herz, Waleed, Kunkel, Louis M, Geha, Raif S
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2016; Nature Publishing Group
• Subjects: 13/109; 631/250/248; 692/699/249/1570; 96/31; Adaptive Immunity - genetics; Agriculture; Analysis; Anemia - genetics; Animal Genetics and Genomics; Animals; Antigens, CD - genetics; Antigens, CD - immunology; Antigens, CD - metabolism; B cells; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Biomedicine; Cancer Research; Cell Cycle Proteins; Cell growth; Cells, Cultured; Endocytosis; Experiments; Families & family life; Female; Fibroblasts - physiology; Gene expression; Gene Function; Genetic aspects; Genomes; Grants; Haplotypes; Human Genetics; Humans; Immunodeficiency; Immunologic Deficiency Syndromes - genetics; Infections; Laboratories; letter; Lymphocytes; Male; Medical research; Medical schools; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Mutation, Missense; Neonatology; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Oxidoreductases; Pedigree; Receptors, Transferrin - genetics; Receptors, Transferrin - immunology; Receptors, Transferrin - metabolism; T cell receptors; Tetanus toxoid; Transferrin
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3465

Raif Geha, Louis Kunkel, Waleed Al-Herz and colleagues report a mutation in TFRC (encoding transferrin receptor 1, TfR1) that causes combined immunodeficiency characterized by impaired function of T and B cells in homozygous patients. Iron citrate rescued the lymphocyte defects in patient-derived cells and in a mouse model, demonstrating the importance of TfR1-mediated iron internalization in adaptive immunity. Patients with a combined immunodeficiency characterized by normal numbers but impaired function of T and B cells had a homozygous p.Tyr20His substitution in transferrin receptor 1 (TfR1), encoded by TFRC . The substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts. Tfrc Y20H/Y20H mice recapitulated the immunological defects of patients. Despite the critical role of TfR1 in erythrocyte development and function, patients had only mild anemia and only slightly increased TfR1 expression in erythroid precursors. We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares patients from severe anemia. These findings demonstrate the importance of TfR1 in adaptive immunity.