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

Haifa H Jabara 1 2, Steven E Boyden 3 4 5, Janet Chou 1 2, Narayanaswamy Ramesh 1 2, Michel J Massaad 1 2, Halli Benson 1, Wayne Bainter 1, David Fraulino 1, Fedik Rahimov 3 4, Colin Sieff 2 6, Zhi-Jian Liu 2 7, Salem H Alshemmari 8, Basel K Al-Ramadi 9, Hasan Al-Dhekri 10, Rand Arnaout 10, Mohammad Abu-Shukair 11, Anant Vatsayan 12, Eli Silver 13, Sanjay Ahuja 12, E Graham Davies 14, Martha Sola-Visner 2 7, Toshiro K Ohsumi 5 15, Nancy C Andrews 16 17, Luigi D Notarangelo 1 2, Mark D Fleming 18, Waleed Al-Herz 19, Louis M Kunkel 2 3 4 5, Raif S Geha 1 2

Affiliations

01 January 2016

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doi: 10.1038/ng.3465

Abstract

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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