The article and editorial describe a new cause of combined immunodeficiency (CID). Authors explain a form of CID caused by impaired cellular iron import. CIDs are genetic disorders with disrupted development, or function, … of T and B lymphocytes leading to susceptibility to life-threatening infections. Although mutations in more than 40 genes are already known to cause CID, there are still a substantial portion of CID patients who have unknown genetic defects. Authors have identified a homozygous p.Tyr20His substitution in the transferrin receptor-1 (TfR1; encoded by TFRC) as the genetic cause of CID in two families.
The amino-acid 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, curiously, the patients had only mild anemia and only slightly increased TfR1 expression in erythroid precursors. Authors showed that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts. These data suggest that STEAP3 may provide an accessory TfR1 endocytosis signal that spares patients from severe anemia. Their findings demonstrate the importance of TfR1 in adaptive immunity.
Nat Genet Jan 2o16; 48: 74–78 & 10–11