A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency
Open accessAbstract
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.
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The MIGA1 gene plays a major role for the development and proliferation of lymphocytes since defective T- and B-cell activation is caused by inadequate iron uptake.
“This gene also plays a major role for the development and proliferation of lymphocyte since defective T- and B-cell activation is caused by inadequate iron uptake (Rouault, 2006; Jabara et al., 2016).”
From Identification of Candidate Signature Genes and Key Regulators Associated With Trypanotolerance in the Sheko Breed (2019) · cites this paper as Jabara et al., 2016
The paper states that insufficient iron uptake causes defective T- and B-cell activation and that transferrin receptor 1 is essential for lymphocyte development and proliferation (passages 1 and 3, section labeled Abstract; page unavailable). It studies TFRC, which encodes transferrin receptor 1, not MIGA1, so it does not support attributing that role to MIGA1. (LLM, conf=0.90)
Experimental — accuracy not yet measuredHuman mutations in the TFR1 gene have been associated with severe combined immunodeficiency.
“Of note, humans mutations in the TFR1 gene have been associated with severe combined immunodeficiency (Jabara et al., 2015).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Jabara et al., 2015
A mutation in the human TFRC gene, which codes for TFR, was identified in patients with combined immunodeficiencies (CID).
“Importantly, a mutation in the human TFRC gene, which codes for TFR, was identified in patients with combined immunodeficiencies (CID) (Jabara et al., 2015).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Jabara et al., 2015
Tfr1 is widely expressed by isolated macrophages and may form a major route of iron uptake in the absence of RBC, though it also appears important in adaptive immunity.
“Tfr1, which is also known as CD71, is widely expressed by isolated macrophages, and it may form a major route of iron uptake in the absence of RBC (an indirect iron source), though it also appears to be important in adaptive immunity [103, 138].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [103]
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References 24 · Cited by 279
Research works printed but not linked: 1
- [1]Al-Herz W Bousfiha A Casanova J–L Chatila T Front Immunol 5 1 133 2014 24795713 PMC4001072
- Authors
- Jabara, H. H., Boyden, S. E., Chou, J., Ramesh, N., Massaad, M. J., Benson, H., Bainter, W., Fraulino, D., Rahimov, F., Sieff, C., Liu, Z.-J., Alshemmari, S. H., Al-Ramadi, B. K., Al-Dhekri, H., Arnaout, R., Abu-Shukair, M., Vatsayan, A., Silver, E., Ahuja, S., Davies, E. G., Sola-Visner, M., Ohsumi, T. K., Andrews, N. C., Notarangelo, L. D., Fleming, M. D., Al-Herz, W., Kunkel, L. M., & Geha, R. S.
- Affiliations
- Boston Children's Hospital (US)
- Kuwait University (KW)
- United Arab Emirates University (AE)
- King Faisal Specialist Hospital & Research Centre (SA)
- Rainbow Babies & Children's Hospital (US)
- Great Ormond Street Hospital (GB)
- Harvard University (US)
- Duke University (US)
- Corresponding author
- Geha, Raif S
- ORCID
- Boyden, Steven E
- Chou, Janet
- Massaad, Michel J
- Bainter, Wayne
- Fraulino, David
- Rahimov, Fedik
- Sieff, Colin
- Alshemmari, Salem H
- Al-Ramadi, Basel K
- Arnaout, Rand
- Vatsayan, Anant
- Ahuja, Sanjay
- Davies, E Graham
- Sola-Visner, Martha
- Ohsumi, Toshiro K
- Andrews, Nancy C
- Notarangelo, Luigi D
- Fleming, Mark D
- Kunkel, Louis M
- Geha, Raif S
- Venue
- Nature Genetics
- Published
- 2015-12-07
- Volume
- 48
- Issue
- 1
- Pages
- 74-78
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC4696875
- OpenAlex
- W2194900304
- Cited by
- 279
- References
- 24
- Citations by year
- 2026: 31 · 2025: 34 · 2024: 29 · 2023: 32 · 2022: 35 · 2021: 34 · 2020: 25 · 2019: 26 · 2018: 9 · 2017: 15 · 2016: 7 · 2015: 1
- FWCI
- 8.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Howard Hughes Medical Institute
- National Institute of Allergy and Infectious Diseases (P01AI076210, HHSN-272201300006C, T32AI007512)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK089705, R01DK087992)
- National Institute of Neurological Disorders and Stroke (P50 NS40828, P50NS040828)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD090255, P30HD018655, P30HD-18655)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- transferrin receptor 1, transferrin receptor, missense mutations, combined immunodeficiency, T cell dysfunction, B cell dysfunction, transferrin uptake, receptor internalization, STEAP3, erythroblasts, anemia, adaptive immunity
- MeSH terms
- Anemia, Animals, B-Lymphocytes, Cells, Cultured, Endocytosis, Female, Fibroblasts, Humans, Immunologic Deficiency Syndromes, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Oxidoreductases, Pedigree, Receptors, Transferrin, Oncogene Proteins, Antigens, CD, Cell Cycle Proteins, Mutation, Missense, Adaptive Immunity
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