TFRC Gene

The TFRC gene (TFRC stands for "Transferrin Receptor") is a protein coding gene located on chromosome 3q29. The TFRC gene encodes a cell surface receptor that is necessary for cellular iron uptake through the process of receptor-mediated endocytosis. This receptor is required for erythropoiesis and neurological development. Several alternatively spliced variants have been identified.

Diseases associated with TFRC include:

• Immunodeficiency 46 (OMIM: 616740; Jabara HH et al. 2016).

Related signaling pathways include the HIF-1-alpha transcription factor network and vesicle-mediated transport. Cellular uptake of iron occurs through receptor-mediated endocytosis of the ligand-occupied transferrin receptor into specialized endosomes. Endosomal acidification leads to iron release. The apotransferrin-receptor complex is then returned to the cell surface with the return to neutral pH and concomitant loss of affinity of apotransferrin for its receptor.

The transferrin receptor is necessary for erythrocyte and nervous system development. A second ligand, the heditary hemochromatosis protein HFE, competes with transferrin for binding at an overlapping C-terminal binding site. Positively regulates proliferation of T and B cells through iron uptake. Acts as a lipid sensor that regulates mitochondrial fusion by controlling activation of the JNK pathway. When dietary stearate concentration is low, it promotes activation of JNK pathway, leading to HUWE1-mediated ubiquitination and subsequent degradation of mitofusin MFN2 and inhibition of mitochondrial fusion. At high levels of stearate (C18:0) in the diet, stearoylation of TFRC inhibits activation of the JNK pathway and consequent degradation of mitofusin MFN2.

1. Aljohani AH et al (2020) Clinical and Immunological Characterization of Combined Immunodeficiency Due to TFRC Mutation in Eight Patients. J Clin Immunol 40:1103-1110.
2. Jabara HH et al. (2016) A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. Nature Genet 48: 74-78.
3. Whangbo JS et al (2021) Hematopoietic Stem Cell Transplantation Is a Curative Therapy for Transferrin Receptor 1 (TFRC) Deficiency. J Allergy Clin Immunol Pract 9:753-759.