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. TfrcY20H/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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We thank F. Alkuraya, H. Oettgen and T. Chatila for valuable discussions and the immunology laboratory staff at the Faculty of Medicine of Kuwait University for technical assistance. This work was supported by US National Institutes of Health (NIH) grants AI-076210, AI-007512 (R.S.G.), 1K08AI116979-01 (J.C.) and DK-089705 (N.C.A.), a grant from the Dubai Harvard Foundation for Medical Research (R.S.G.), the Perkins Fund (R.S.G.), the Howard Hughes Medical Institute (L.M.K.), the Manton Center for Orphan Disease Research (L.M.K.), the Kuwait Foundation for Advancement of Sciences 2010-1302-05 (W.A.-H.), a Jeffrey Modell Foundation Translational Research Program Grant award (J.C.) and a Manton Center Pilot Award (J.C.). Microarray genotyping and Sanger DNA sequencing were performed in the Molecular Genetics Core Facility at Boston Children's Hospital, supported by US NIH grant P30-HD18655 through the Intellectual and Developmental Disabilities Research Center and US NIH grant P50-NS40828 through the Neuromuscular Disease Project. We acknowledge the US NIH Tetramer Core Facility (contract HHSN272201300006C) for provision of the mouse CD1d tetramers.
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Supplementary Figures 1–6, Supplementary Tables 1–6 and Supplementary Note.
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Nature Genetics (2016)