TMPRSS6 – Iron-Refractory Iron Deficiency Anemia (IRIDA)

Iron-refractory iron deficiency anemia (IRIDA) is a rare autosomal recessive disorder characterized by hypochromic microcytic anemia unresponsive to oral iron and inappropriately elevated hepcidin. The causative gene, TMPRSS6 (matriptase-2) HGNC:16517, encodes a hepatic serine protease that downregulates hepcidin by cleaving the BMP co-receptor hemojuvelin. In IRIDA, loss-of-function TMPRSS6 variants lead to unchecked hepcidin expression, impaired iron absorption, and refractory anemia.

Genetic evidence supports a definitive gene–disease relationship. Over 50 probands from more than 30 unrelated families have been reported with biallelic TMPRSS6 mutations in IRIDA (PMID:20232450). Segregation analysis in multiplex pedigrees, including a Sardinian kindred with five affected siblings, demonstrated recessive inheritance and co-segregation of pathogenic alleles (PMID:18603562). Case reports and series describe >20 distinct variants spanning missense, nonsense, splice, and frameshift classes, with compound heterozygotes and homozygotes observed across diverse ethnicities.

Variant spectrum is broad: missense substitutions cluster in functional domains (e.g., c.1537G>A (p.Glu513Lys)) (PMID:19357398), nonsense and frameshift alleles truncate the protease domain, and splice-site changes abrogate zymogen activation. A founder effect has been noted for p.Cys510Ser in Southern Italian patients (PMID:20232450), while other recurrent alleles (e.g., p.Gly433Arg, p.Tyr141Cys) recur across families. The variant c.1537G>A (p.Glu513Lys) impairs membrane targeting and autocatalytic cleavage (PMID:19357398).

Functional assays robustly demonstrate loss of TMPRSS6 activity. In vitro mutagenesis and transfection studies reveal that LDLRA domain mutations retain hemojuvelin binding but fail to auto-activate and only partially repress hepcidin promoter activity (PMID:19357398). SEA domain mutants (p.Tyr141Cys) localize correctly but lack protease activation and elevate hepcidin mRNA (PMID:20704562). Knockout and double-mutant mouse models confirm that absence of Tmprss6 increases BMP-SMAD signaling and hepcidin, leading to microcytic anemia (PMID:20200349).

There is no substantive conflicting evidence. TMPRSS6 variants consistently segregate with IRIDA phenotype, and no alternative molecular causes have been demonstrated in affected individuals lacking mutations in other iron-homeostasis genes.

In summary, biallelic TMPRSS6 mutations cause IRIDA through loss of matriptase-2 proteolytic regulation of hepcidin. Genetic testing of TMPRSS6 is diagnostic in patients with unexplained hypochromic microcytic anemia and high hepcidin. Recognition of IRIDA enables tailored management, including parenteral iron and ascorbic acid supplementation, and informs carrier screening in families.

Key Take-home: TMPRSS6 loss-of-function alleles definitively underlie IRIDA, supporting genetic testing and functional assays to guide diagnosis and therapy.

References

• Haematologica • 2008 • A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease that suppresses hepcidin production, in familial iron deficiency anemia refractory to oral iron. PMID:18603562
• Blood • 2009 • Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6 mutations associated with iron-refractory iron deficiency anemia. PMID:19357398
• Human Mutation • 2010 • Novel TMPRSS6 mutations associated with iron-refractory iron deficiency anemia (IRIDA). PMID:20232450
• Blood • 2010 • Down‐regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis. PMID:20200349
• The Biochemical Journal • 2010 • A novel TMPRSS6 mutation that prevents protease auto-activation causes IRIDA. PMID:20704562
• Human Molecular Genetics • 2009 • Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms. PMID:19592582

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