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

Haifa H. Jabara, Steven E. Boyden, Janet Chou, Narayanaswamy Ramesh, Michel J. Massaad, Halli Benson, Wayne Bainter, David Fraulino, Fedik Rahimov, Colin Sieff, Zhi Jian Liu, Salem H. Alshemmari, Basel K. Al-Ramadi, Hasan Al-Dhekri, Rand Arnaout, Mohammad Abu-Shukair, Anant Vatsayan, Eli Silver, Sanjay Ahuja, E. Graham DaviesMartha Sola-Visner, Toshiro K. Ohsumi, Nancy C. Andrews, Luigi D. Notarangelo, Mark D. Fleming, Waleed Al-Herz, Louis M. Kunkel, Raif S. Geha

Research output: Contribution to journalArticlepeer-review

173 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)74-78
Number of pages5
JournalNature Genetics
Issue number1
Publication statusPublished - Dec 29 2015

ASJC Scopus subject areas

  • Genetics


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