A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency
| Autor: | Anant Vatsayan, Fedik Rahimov, Waleed Al-Herz, Colin A. Sieff, Mark D. Fleming, Basel K. al-Ramadi, E. Graham Davies, Michel J. Massaad, Martha Sola-Visner, Raif S. Geha, Narayanaswamy Ramesh, Haifa H. Jabara, Nancy C. Andrews, Wayne Bainter, Eli Silver, David Fraulino, Steven E. Boyden, Rand Arnaout, Salem H. Alshemmari, Sanjay P Ahuja, Louis M. Kunkel, Hasan Al-Dhekri, Mohammad Abu-Shukair, Zhi-Jian Liu, Janet Chou, Toshiro K. Ohsumi, Halli Benson, Luigi D. Notarangelo |
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| Rok vydání: | 2015 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Lymphocyte media_common.quotation_subject Mutation Missense Cell Cycle Proteins Transferrin receptor Adaptive Immunity Biology Endocytosis 03 medical and health sciences Antigens CD Internal medicine Receptors Transferrin Genetics medicine Animals Humans Missense mutation Receptor Internalization Cells Cultured Immunodeficiency media_common Oncogene Proteins chemistry.chemical_classification B-Lymphocytes Immunologic Deficiency Syndromes Anemia Fibroblasts medicine.disease Molecular biology Mice Mutant Strains Pedigree 3. Good health Mice Inbred C57BL 030104 developmental biology Endocrinology medicine.anatomical_structure chemistry Transferrin Female Oxidoreductases |
| Zdroj: | Nature Genetics. 48:74-78 |
| ISSN: | 1546-1718 1061-4036 |
| DOI: | 10.1038/ng.3465 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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