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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Jabara, HH; Boyden, SE; Chou, J; Ramesh, N; Massaad, MJ; Benson, H; Bainter, W; Fraulino, D; Rahimov, F; Sieff, C; Liu, Z-J; Alshemmari, SH; Al-Ramadi, BK; Al-Dhekri, H; Arnaout, R; Abu-Shukair, M; Vatsayan, A; Silver, E; Ahuja, S; Davies, EG; Sola-Visner, M; Ohsumi, TK; Andrews, NC; Notarangelo, LD; Fleming, MD; Al-Herz, W; Kunkel, LM; Geha, RS

Published Date

  • January 2016

Published In

Volume / Issue

  • 48 / 1

Start / End Page

  • 74 - 78

PubMed ID

  • 26642240

Pubmed Central ID

  • PMC4696875

Electronic International Standard Serial Number (EISSN)

  • 1546-1718

Digital Object Identifier (DOI)

  • 10.1038/ng.3465


  • eng

Conference Location

  • United States