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.

Author information

Author notes

    • Haifa H Jabara
    • , Steven E Boyden
    •  & Janet Chou

    These authors contributed equally to this work.

    • Waleed Al-Herz
    • , Louis M Kunkel
    •  & Raif S Geha

    These authors jointly supervised this work.


  1. Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Haifa H Jabara
    • , Janet Chou
    • , Narayanaswamy Ramesh
    • , Michel J Massaad
    • , Halli Benson
    • , Wayne Bainter
    • , David Fraulino
    • , Luigi D Notarangelo
    •  & Raif S Geha
  2. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

    • Haifa H Jabara
    • , Janet Chou
    • , Narayanaswamy Ramesh
    • , Michel J Massaad
    • , Colin Sieff
    • , Zhi-Jian Liu
    • , Martha Sola-Visner
    • , Luigi D Notarangelo
    • , Louis M Kunkel
    •  & Raif S Geha
  3. Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Steven E Boyden
    • , Fedik Rahimov
    •  & Louis M Kunkel
  4. Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Steven E Boyden
    • , Fedik Rahimov
    •  & Louis M Kunkel
  5. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Steven E Boyden
    • , Toshiro K Ohsumi
    •  & Louis M Kunkel
  6. Division of Hematology, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Colin Sieff
  7. Division of Neonatology, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Zhi-Jian Liu
    •  & Martha Sola-Visner
  8. Department of Medicine, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.

    • Salem H Alshemmari
  9. Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.

    • Basel K Al-Ramadi
  10. King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

    • Hasan Al-Dhekri
    •  & Rand Arnaout
  11. Immunology, Allergy and Rheumatology Division, Queen Rania Hospital for Children, Amman, Jordan.

    • Mohammad Abu-Shukair
  12. Department of Pediatric Hematology/Oncology, University Hospitals Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio, USA.

    • Anant Vatsayan
    •  & Sanjay Ahuja
  13. Division of Pulmonology and Sleep Medicine, University Hospitals Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio, USA.

    • Eli Silver
  14. Centre for Immunodeficiency, Great Ormond Street Hospital and Institute of Child Health, London, UK.

    • E Graham Davies
  15. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Toshiro K Ohsumi
  16. Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.

    • Nancy C Andrews
  17. Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.

    • Nancy C Andrews
  18. Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Mark D Fleming
  19. Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.

    • Waleed Al-Herz


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H.H.J. performed functional experiments on the index family and on the TfrcY20H/Y20H mouse model. S.E.B. identified the TFRC mutation in the index family and performed genetic experiments and genome-wide linkage and whole-genome sequencing analyses. J.C. generated and analyzed the TfrcY20H/Y20H mouse model together with W.B. and D.F., performed functional experiments on patient B1 and provided clinical care to the patients in the index family. N.R., M.J.M., H.B., C.S. and Z.-J.L. performed functional experiments on the index family. F.R. performed genetic experiments. S.H.A. and B.K.A.-R. provided ancestry-matched control DNA samples. H.A.-D., R.A., M.A.-S., A.V., E.S. and S.A. identified and provided clinical care for patient B1. E.G.D. provided tissue specimens from the affected patients in family A who had undergone HSCT. T.K.O. performed bioinformatics analysis. M.S.-V., N.C.A., L.D.N., M.D.F. and W.A.-H. gave critical advice. W.A.-H. ascertained and provided clinical care to the index family. H.H.J., S.E.B., J.C., L.M.K. and R.S.G. wrote the manuscript. R.S.G. and L.M.K. designed and coordinated the investigations. The final version of the manuscript was approved by all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Raif S Geha.

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