Submission Details

The TFR2 gene encodes transferrin receptor 2, which is predominantly expressed in the liver. This receptor mediates the cellular uptake of transferrin-bound iron and plays a key role in the synthesis of hepcidin (PMID: 36483608). TFR2 was first implicated in autosomal recessive hemochromatosis type 3 (HH3) in 2000 (Camaschella et al., PMID: 10802645). HH3 is characterized by elevated transferrin saturation, serum ferritin, iron levels, and liver transaminases, along with increased hepatic iron deposition and decreased serum hepcidin. Clinical manifestations include cirrhosis, liver fibrosis, hepatosplenomegaly, cardiomyopathy, hyperpigmentation, hypogonadism, arthritis, diabetes, and hematological abnormalities. A variety of pathogenic variants have been reported in affected individuals, including missense, nonsense, splicing, frameshift variants, and in-frame deletions. This curation includes 25 unrelated probands and 24 unique variants (PMIDs: 10802645, 11313241, 11984516, 12130528, 15685557, 16923517, 18245657, 18450729, 19144662, 23600741, 26029709, 34946929, 35464850). The gene-disease relationship is supported by case-level data and segregation studies, reaching the maximum score of 12 points for case level evidence. Additional support comes from animal models, expression studies, and functional assays (PMIDs: 10409623, 12134060, 15951546, 18064142, 16935854, 20177050, 20179178, 26408288). Northern blot analysis of human tissues confirmed predominant liver expression of TFR2, and the protein was shown to bind iron-loaded transferrin to facilitate hepatic iron uptake (PMID: 10409623). Multiple TFR2 knockout (KO) mouse models recapitulate the human phenotype, including elevated transferrin saturation, iron levels, ferritin, and hepatic iron accumulation (PMIDs: 12134060, 16935854, 15951546, 20133002, 20179178). These models also exhibit dysregulation of iron metabolism genes coding for hepcidin and ferroportin (PMIDs: 16935854, 20179178, 20133002). Liver-specific knock-in of wild-type TFR2 rescued the iron overload phenotype and restored hepcidin expression (PMID: 20177050). In vitro studies demonstrated that variants identified in HH3 patients led to reduced TFR2 protein accumulation, abnormal glycosylation, retention of mutant proteins in the endoplasmic reticulum and absence of mutant protein on the cell membrane (PMIDs: 26029709, 18094142, 26408288). Although additional experimental evidence exists, the maximum score of 6 points for experimental evidence has already been reached. In summary, there is definitive evidence supporting the relationship between TFR2 and autosomal recessive hemochromatosis type 3. This association has been consistently demonstrated in both research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen General Inborn Errors of Metabolism Gene Curation Expert Panel on the meeting date August 22, 2025 (SOP Version 11).