rs387907018 — TMPRSS6 Matriptase-2 E522K

TMPRSS6 E522K — The Iron-Refractory Anemia Variant

Your body's ability to absorb dietary iron is governed by a small hormone called hepcidin¹¹ hepcidin
A 25-amino-acid peptide produced by the liver that acts as the master regulator of systemic iron levels. It binds and degrades ferroportin, the sole known cellular iron exporter, on gut enterocytes and macrophages, blocking iron absorption and iron recycling. Under normal conditions, when iron stores are low, hepcidin falls and the gut absorbs more iron. This feedback loop is maintained by matriptase-2²² matriptase-2
The protein product of TMPRSS6; a type II transmembrane serine protease expressed predominantly in the liver that cleaves membrane hemojuvelin, removing a critical activating signal for hepcidin transcription.

The rs387907018 variant (also called E522K, referring to the same amino acid change in different isoform numbering systems) is a missense mutation in TMPRSS6 that substitutes lysine for glutamic acid in the second LDL-receptor class A (LDLRA2) domain³³ second LDL-receptor class A (LDLRA2) domain
One of three LDLRA repeats in the extracellular region of matriptase-2; contains a conserved D/NXSDE calcium-binding motif essential for proper protein folding and cell-surface targeting. This is one of over 70 pathogenic TMPRSS6 variants; together they cause iron-refractory iron deficiency anemia⁴⁴ iron-refractory iron deficiency anemia
IRIDA — OMIM #206200. A rare autosomal recessive disorder characterised by hypochromic microcytic anemia that does not respond to oral iron supplementation because constitutively elevated hepcidin prevents gut iron absorption regardless of iron status (IRIDA).

The Mechanism

Matriptase-2 keeps hepcidin in check by cleaving membrane hemojuvelin⁵⁵ membrane hemojuvelin
A GPI-anchored protein that acts as a co-receptor for bone morphogenetic proteins (BMPs). When intact on the hepatocyte surface, it amplifies BMP-SMAD signalling to increase hepcidin transcription. Matriptase-2 removes it by proteolytic cleavage, blunting the hepcidin signal, a BMP co-receptor that potently stimulates hepcidin transcription. When matriptase-2 is functional, it cleaves membrane hemojuvelin in proportion to the body's iron needs, providing a tunable brake on hepcidin. When it is disabled, hemojuvelin accumulates on the hepatocyte surface and hepcidin is produced constitutively, even in the face of severe iron deficiency.

The E522K substitution sits in the conserved D/NXSDE calcium-binding motif of the LDLRA2 domain. Loss of this calcium coordination partially misfolds the extracellular region, causing the protein to be retained in the Golgi apparatus⁶⁶ retained in the Golgi apparatus
The cell's protein sorting and packaging station, located between the endoplasmic reticulum and the plasma membrane. Proteins retained there are not delivered to the cell surface and cannot carry out their membrane-bound functions rather than reaching the plasma membrane. Cell biology studies⁷⁷ Cell biology studies
Silvestri et al. Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6 mutations associated with iron-refractory iron deficiency anemia. Blood, 2009 confirmed that E522K matriptase-2 shows absent autoactivation, absent hemojuvelin cleavage, and only partial hepcidin repression in transfection assays — despite retaining the physical ability to bind hemojuvelin.

The end result is a broken feedback loop: the gut cannot absorb dietary iron because hepcidin is always elevated, and oral iron supplements cannot overcome the block. This is why IRIDA is by definition refractory to oral iron.

The Evidence

TMPRSS6 was identified as the IRIDA gene by Finberg et al. in 2008⁸⁸ Finberg et al. in 2008
Finberg KE et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet, 2008, studying five multiplex kindreds and two sporadic cases with IRIDA unresponsive to oral iron. All affected individuals had biallelic loss-of-function TMPRSS6 mutations and inappropriately elevated urinary hepcidin despite severe iron deficiency and microcytic anemia.

The E522K variant specifically was characterised by Silvestri et al. in 2009⁹⁹ Silvestri et al. in 2009
Silvestri L et al. Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6 mutations associated with iron-refractory iron deficiency anemia. Blood, 2009. The mutation was identified in compound heterozygosity (alongside D521N at the same LDLRA2 domain) in a patient with clinical IRIDA. Both variants caused Golgi retention of the protein and complete loss of hemojuvelin cleavage activity, while still allowing hemojuvelin binding — demonstrating that the LDLRA2 domain is required for cell surface localisation and catalytic activation but not for substrate recognition.

In gnomAD (v4 exomes), the T allele is observed in 40 out of 1,400,880 alleles (~2.9 per 100,000), confirming its classification as an ultra-rare pathogenic variant. No homozygotes have been observed in gnomAD, consistent with the rarity and clinical severity of biallelic TMPRSS6 loss.

Practical Implications

IRIDA is managed with parenteral iron¹⁰¹⁰ parenteral iron
Iron delivered intravenously, bypassing the gut entirely. Intravenous iron reaches macrophages directly; the subsequent rise in ferroportin expression partially overcomes hepcidin's block on iron release, restoring iron availability to erythroid progenitors rather than oral iron, since hepcidin elevation completely blocks intestinal absorption. Current expert guidance¹¹¹¹ expert guidance
Expert opinion-based treatment guidance for IRIDA in children and adults, 2025 recommends IV iron in smaller, frequent doses (maximum 500 mg elemental iron per session at two-week intervals) to avoid paradoxically raising hepcidin further. Treatment targets quality of life and a transferrin saturation of ~15% rather than normalisation of hemoglobin. Biallelic carriers typically present in childhood with severe microcytic anemia (MCV 45-65 fL) and transferrin saturation below 5%.

Heterozygous carriers of IRIDA-causing TMPRSS6 variants generally have normal iron parameters, though emerging evidence¹²¹² emerging evidence
Transferrin Saturation/Hepcidin Ratio study distinguishing monoallelic IRIDA from multi-causal IDA. Blood, 2022 shows that some monoallelic carriers have intermediate hepcidin dysregulation and can present with a milder IRIDA phenotype — particularly women, where menstrual iron losses add environmental pressure to the partial pathway impairment.

Interactions

The most clinically important interaction is between this variant and a second TMPRSS6 pathogenic allele. IRIDA requires biallelic loss of matriptase-2 function — compound heterozygosity (one E522K allele plus another pathogenic TMPRSS6 variant) produces full IRIDA just as homozygosity does. If a heterozygous carrier reproduces with another TMPRSS6 pathogenic variant carrier, there is a 25% chance per pregnancy of a child with IRIDA.

TMPRSS6 variants also interact indirectly with the common TMPRSS6 rs855791 (Ala736Val) polymorphism, which modulates the same hepcidin regulatory pathway. Carrying an IRIDA-causing allele (rs387907018) alongside the iron-lowering haplotype of rs855791 could theoretically worsen iron status in heterozygous carriers, although direct evidence for this specific combination is not published.

HFE variants rs1800562 (C282Y) and rs1799945 (H63D) affect the same BMP-hepcidin axis from the opposite direction — HFE mutations reduce hepcidin and cause iron overload, while TMPRSS6 loss-of-function variants constitutively elevate hepcidin and cause iron deficiency. Compound heterozygosity across these genes (one HFE and one TMPRSS6 allele) is not well-studied but could produce offsetting effects on iron status.