rs387907018 — TMPRSS6 Matriptase-2 E522K

Rare pathogenic TMPRSS6 missense in the LDLRA2 domain that impairs hemojuvelin cleavage and causes iron-refractory iron deficiency anemia (IRIDA) by preventing hepcidin suppression

See your personal result for TMPRSS6

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

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.

Nutrient Interactions

iron impaired_conversion

Genotype Interpretations

What each possible genotype means for this variant.

CC Non-Carrier Normal

Normal TMPRSS6 function — no IRIDA risk from this variant

With two functional TMPRSS6 alleles, your matriptase-2 protein is properly folded, traffics normally to the hepatocyte plasma membrane, and maintains the hepcidin-ferroportin iron regulatory axis. During iron deficiency, matriptase-2 upregulates and cleaves more hemojuvelin, reducing hepcidin and permitting increased iron absorption from the gut — the normal adaptive response.

The pathogenic T allele is so rare (gnomAD allele frequency ~2.9 per 100,000) that the probability of homozygosity in the absence of a known family history is effectively zero.

CT IRIDA Carrier Carrier

Heterozygous carrier of E522K — one functional and one non-functional TMPRSS6 allele

Your single functional TMPRSS6 allele produces sufficient matriptase-2 to maintain iron homeostasis under most conditions. However, emerging data on monoallelic TMPRSS6 IRIDA patients suggests that haploinsufficiency may produce subtle hepcidin dysregulation: affected heterozygotes have lower transferrin saturation/hepcidin ratios than unaffected relatives carrying the identical variant, pointing to additional genetic or environmental modifiers.

Women are over-represented among symptomatic monoallelic carriers (75% female in the largest series), consistent with menstrual iron losses stressing a partially impaired hepcidin-regulation pathway. If iron deficiency is diagnosed and does not respond well to oral iron, TMPRSS6 haploinsufficiency is worth considering as a partial contributor — particularly if serum hepcidin is measurably elevated relative to the degree of iron deficiency.

The most important clinical implication of carrier status is reproductive: if your reproductive partner is also a TMPRSS6 pathogenic variant carrier, there is a 25% per-pregnancy chance of a child with biallelic IRIDA.

TT Biallelic IRIDA Homozygous

Homozygous for E522K — high likelihood of iron-refractory iron deficiency anemia

With both TMPRSS6 alleles carrying the E522K substitution, your matriptase-2 is retained in the Golgi apparatus rather than reaching the hepatocyte surface. It cannot cleave membrane hemojuvelin, so the BMP-SMAD signalling pathway to hepcidin transcription runs continuously and unchecked. Hepcidin degrades ferroportin on gut enterocytes, closing the door on dietary iron absorption regardless of how iron-depleted you are.

Classic IRIDA presents in childhood (or even infancy) with markedly low MCV (45-65 fL), low transferrin saturation (typically below 5%), and a normal or low-normal ferritin — an unusual combination because the low ferritin confirms depleted stores, while the TSAT confirms the absorbed iron cannot reach erythroid progenitors. Serum or urinary hepcidin levels are inappropriately elevated or within normal range despite the iron-deficient state (normal hepcidin in the context of iron deficiency is itself pathologically elevated).

Treatment is parenteral iron, not oral iron. IV iron delivers iron directly to macrophages, bypassing the gut; subsequent ferroportin upregulation can partially overcome the hepcidin block and restore some iron supply to red cell precursors. Response is typically partial — hemoglobin improves but rarely normalises. Some patients require lifelong fortnightly IV iron infusions. Experimental anti-hepcidin antibodies and hepcidin antagonists are under investigation but not yet approved.