TFR2 – Hemochromatosis Type 3

Hereditary hemochromatosis type 3 is an autosomal recessive iron‐overload disorder caused by biallelic mutations in the transferrin receptor 2 gene TFR2 leading to excessive hepatic iron deposition and early periportal hepatocyte loading seen clinically and histologically in affected individuals (PMID:11984516). The diagnosis is supported by genetic testing when HFE mutations are absent and clinical features of iron overload occur.

Genetic evidence comprises multiple unrelated probands with distinct TFR2 variant classes. A first family carried a homozygous 12‐nucleotide deletion in exon 16 (c.1849GCCGTGGCCCAGdel (p.611_AlaValAlaGlndel)) segregating with disease in three affected members and absent in 100 controls (PMID:11984516). Subsequent studies described five private homozygous mutations (Y250X, E60X, M172K, AVAQ594-597del, Q690P) in five probands (PMID:12547237). More recently, three Spanish families revealed four additional pathogenic alleles, including a truncating variant c.2014C>T (p.Gln672Ter) identified in homozygous and compound heterozygous states in adult and pediatric cases (PMID:26029709).

Segregation analysis across pedigrees documented at least 16 affected relatives harboring biallelic TFR2 variants, confirming cosegregation with iron overload in both inbred and outbred families (PMID:11984516; PMID:11313241). All variants are loss-of-function through nonsense‐mediated decay, frameshift, or splicing disruption, consistent with autosomal recessive inheritance.

Functional and experimental studies demonstrate concordant pathogenic mechanisms. A murine Tfr2(Y245X) model recapitulates human hepatic iron loading, elevated transferrin saturation, and low splenic iron, confirming the role of TFR2 in systemic iron homeostasis (PMID:12134060). Cellular localization assays of missense (p.Gly792Arg) and splice‐site (c.1606-8A>G) variants show impaired membrane targeting and aberrant mRNA, resulting in defective hepcidin signaling (PMID:18094142; PMID:26029709).

The mechanism of pathogenicity is consistent with receptor loss leading to insufficient hepcidin induction, unregulated ferroportin activity, and progressive iron accumulation. There is no conflicting evidence disputing TFR2’s role in type 3 hemochromatosis. No notable genotype–phenotype exceptions have been reported beyond variable penetrance in premenopausal women.

In summary, TFR2 variants fulfill ClinGen criteria for a Strong gene–disease association based on numerous unrelated probands, extensive segregation data, and robust functional corroboration. TFR2 genotyping should be incorporated into diagnostic algorithms for unexplained iron overload.

Key take-home: Autosomal recessive TFR2 loss-of-function variants cause hemochromatosis type 3 by disrupting hepcidin regulation, and clinical testing of TFR2 facilitates diagnosis in HFE-negative iron‐overloaded patients.

References

• Gastroenterology • 2002 • Clinical and pathologic findings in hemochromatosis type 3 due to a novel mutation in transferrin receptor 2 gene. PMID:11984516
• Blood cells, molecules & diseases • 2002 • Hemochromatosis due to mutations in transferrin receptor 2. PMID:12547237
• Blood • 2001 • New mutations inactivating transferrin receptor 2 in hemochromatosis type 3. PMID:11313241
• Proc Natl Acad Sci U S A • 2002 • Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis. PMID:12134060
• Am J Physiol Cell Physiol • 2008 • Defective trafficking and localization of mutated transferrin receptor 2: implications for type 3 hereditary hemochromatosis. PMID:18094142
• Mol Genet Genomic Med • 2015 • Functional consequences of transferrin receptor-2 mutations causing hereditary hemochromatosis type 3. PMID:26029709

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