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

Nat Genet. 2016 Jan;48(1):74-8. doi: 10.1038/ng.3465.

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

1 Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
2 Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
3 Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.
4 Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA.
5 Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
6 Division of Hematology, Boston Children's Hospital, Boston, Massachusetts, USA.
7 Division of Neonatology, Boston Children's Hospital, Boston, Massachusetts, USA.
8 Department of Medicine, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
9 Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
10 King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
11 Immunology, Allergy and Rheumatology Division, Queen Rania Hospital for Children, Amman, Jordan.
12 Department of Pediatric Hematology/Oncology, University Hospitals Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio, USA.
13 Division of Pulmonology and Sleep Medicine, University Hospitals Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio, USA.
14 Centre for Immunodeficiency, Great Ormond Street Hospital and Institute of Child Health, London, UK.
15 Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
16 Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.
17 Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
18 Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
19 Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.

PMID: 26642240 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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