title: A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency.
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.
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Haifa H
authors.initials: HH
authors.lastname: Jabara
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.|Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Boyden
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Chou
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Narayanaswamy
authors.initials: N
authors.lastname: Ramesh
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Massaad
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Halli
authors.initials: H
authors.lastname: Benson
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Wayne
authors.initials: W
authors.lastname: Bainter
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: David
authors.initials: D
authors.lastname: Fraulino
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.|Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Fedik
authors.initials: F
authors.lastname: Rahimov
authors.affiliation: Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.|Division of Hematology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Colin
authors.initials: C
authors.lastname: Sieff
authors.affiliation: Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.|Division of Neonatology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Zhi-Jian
authors.initials: ZJ
authors.lastname: Liu
authors.affiliation: Department of Medicine, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
authors.forename: Salem H
authors.initials: SH
authors.lastname: Alshemmari
authors.affiliation: Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
authors.forename: Basel K
authors.initials: BK
authors.lastname: Al-Ramadi
authors.affiliation: King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Hasan
authors.initials: H
authors.lastname: Al-Dhekri
authors.affiliation: King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Rand
authors.initials: R
authors.lastname: Arnaout
authors.affiliation: Immunology, Allergy and Rheumatology Division, Queen Rania Hospital for Children, Amman, Jordan.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Abu-Shukair
authors.affiliation: Department of Pediatric Hematology/Oncology, University Hospitals Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Anant
authors.initials: A
authors.lastname: Vatsayan
authors.affiliation: Division of Pulmonology and Sleep Medicine, University Hospitals Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Eli
authors.initials: E
authors.lastname: Silver
authors.affiliation: Department of Pediatric Hematology/Oncology, University Hospitals Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Ahuja
authors.affiliation: Centre for Immunodeficiency, Great Ormond Street Hospital and Institute of Child Health, London, UK.
authors.forename: E Graham
authors.initials: EG
authors.lastname: Davies
authors.affiliation: Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.|Division of Neonatology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Sola-Visner
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.|Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Toshiro K
authors.initials: TK
authors.lastname: Ohsumi
authors.affiliation: Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.|Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Andrews
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.affiliation: Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Fleming
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Herz
authors.affiliation: Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.|Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.|Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Kunkel
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics; D000740:Anemia / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D004705:Endocytosis; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D010088:Oxidoreductases; D010375:Pedigree; D011990:Receptors, Transferrin / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C068126:CD71 antigen; D018797:Cell Cycle Proteins; D015513:Oncogene Proteins; D011990:Receptors, Transferrin; D010088:Oxidoreductases; C486677:STEAP3 protein, human