TFR2 – Hereditary Hemochromatosis

Transferrin receptor 2 (TFR2) is a transmembrane iron‐sensing protein whose bi‐allelic pathogenic variants cause autosomal recessive hereditary hemochromatosis (HH), also known as type 3 hemochromatosis. Affected individuals present with progressive iron overload, elevated transferrin saturation and serum ferritin, and periportal hepatocyte iron deposition often indistinguishable from classic HFE‐related disease (PMID:11984516). TFR2 contributes to hepcidin regulation, coupling circulating diferric transferrin levels to hepatic hepcidin expression.

Multiple unrelated families harbor homozygous or compound heterozygous TFR2 variants: a large inbred Italian pedigree with a homozygous frameshift (p.Glu60Ter) and another with homozygous p.Met172Lys, plus two Italian siblings with p.Met172Lys, and additional kindreds worldwide, totaling >15 probands across five families with disease segregation (PMID:11313241; PMID:16923517). Segregation analyses confirmed autosomal recessive inheritance with clear co‐segregation of TFR2 loss‐of‐function alleles and clinical iron overload.

The variant spectrum includes nonsense (e.g., c.178G>T (p.Glu60Ter)), missense (c.515T>A (p.Met172Lys)), small insertions/deletions and splice‐site changes, all predicted to disrupt receptor function. The recurrent p.Met172Lys (c.515T>A (p.Met172Lys)) was observed homozygous in two siblings with early‐onset severe iron overload and segregates with disease (PMID:16923517).

Type 3 HH due to TFR2 deficiency exhibits low penetrance in premenopausal females but severe iron accumulation in males, with an estimated prevalence of 1:50–1:100 in non–p.Cys282Y European populations. In Central‐Southern Italy, TFR2 mutations accounted for 15.6% of non‐HFE HH cases (PMID:24055163).

Functional studies show that targeted mutagenesis of murine Tfr2 to introduce the orthologous Y245X mutation recapitulates the human phenotype, with elevated hepatic iron concentration and low hepcidin expression by 4 weeks of age (PMID:12134060). In vitro, TFR2 interacts distinctly with transferrin and HFE, and patient‐derived mutations (e.g., Y250X) abolish transferrin binding and accelerate receptor degradation (PMID:15521925).

No conflicting reports have disputed the role of TFR2 in HH; all identified pathogenic alleles in TFR2 cause loss of receptor function, and no benign recurrent variants meeting pathogenic criteria have been described.

Collectively, genetic and experimental data provide strong evidence for TFR2 as an autosomal recessive HH gene with moderate functional support from animal and cellular models. TFR2 genotyping is essential for non‐HFE iron overload cases to guide phlebotomy therapy and family screening.

References

• Gastroenterology • 2002 • Clinical and pathologic findings in hemochromatosis type 3 due to a novel mutation in transferrin receptor 2 gene. PMID:11984516
• Blood • 2001 • New mutations inactivating transferrin receptor 2 in hemochromatosis type 3. PMID:11313241
• Haematologica • 2006 • Homozygous p.M172K mutation of the TFR2 gene in an Italian family with type 3 hereditary hemochromatosis and early onset iron overload. PMID:16923517
• Blood cells, molecules & diseases • 2014 • TFR2-related hereditary hemochromatosis as a frequent cause of primary iron overload in patients from Central-Southern Italy. PMID:24055163
• Proceedings of the National Academy of Sciences • 2002 • Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis. PMID:12134060
• British journal of haematology • 2004 • Analyses for binding of the transferrin family of proteins to the transferrin receptor 2. PMID:15521925

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