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

作者：Jabara Haifa H; Boyden Steven E; Chou Janet; Ramesh Narayanaswamy; Massaad Michel J; Benson Halli; Bainter Wayne; Fraulino David; Rahimov Fedik; Sieff Colin; Liu Zhi Jian; Alshemmari Salem H; Al Ramadi Basel K; Al Dhekri Hasan; Arnaout Rand; Abu Shukair Mohammad; Vatsayan Anant; Silver Eli; Ahuja Sanjay; Davies E Graham; Sola Visner Martha; Ohsumi Toshiro K; Andrews Nancy C; Notarangelo Luigi D; Fleming Mark D; Al Herz Waleed; Kunkel Louis M; Geha Raif S^*

来源：Nature Genetics, 2016, 48(1): 74-+.

DOI：10.1038/ng.3465

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.

• 出版日期2016-1