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Classifications

Harrison's Part

ICIMD (Inherited Metabolic Disorders)

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Definitions

1

Transferrin saturation to hepcidin ratio

A single computable quantity - transferrin saturation in percent divided by plasma hepcidin-25 in nM - with a derived threshold of 5.6 %/nM. Below the threshold suggests IRIDA; above it suggests iron deficiency from another cause. The ratio is the right form for this test because the abnormality it detects is relative. Neither the transferrin saturation nor the hepcidin level is diagnostic alone: a patient with acquired iron deficiency and an IRIDA patient can share a transferrin saturation, and a hepcidin value that is normal in absolute terms is the abnormal finding here. Dividing one by the other is what turns "inappropriately high for the iron status" into a number. Two preconditions are part of the rule, not caveats attached to it. It applies only when the patient has had no iron therapy in the preceding three months and has no moderate-to-severe inflammation, because both raise hepcidin independently of TMPRSS6 and would push a control across the threshold.

PHENOTYPE_ALGORITHM Early discrimination of TMPRSS6-related IRIDA from other causes of iron deficiency anaemia, in a patient already found to be iron deficient.

Inclusion criteria

Established iron deficiency anaemia Iron deficiency anaemia already demonstrated on standard haematological and iron indices.
No iron therapy in the previous three months The derivation cohort's controls were required to be iron-therapy naive over this window, because administered iron raises hepcidin directly.
C-reactive protein below 10.0 mg/L The inflammation ceiling used in the derivation study, excluding moderate-to-severe inflammation.
Hepcidin-25 measured by a mass-spectrometry-calibrated method The threshold is expressed in nM against standardised isotope dilution mass spectrometry and is not portable to an uncalibrated immunoassay.

Exclusion criteria

Recent oral or parenteral iron therapy Raises hepcidin independently of TMPRSS6 and can move an IRIDA patient above the threshold, producing a false negative.
Moderate-to-severe inflammation Raises hepcidin through the inflammatory axis and reproduces the IRIDA pattern in a patient who does not have it.

Show evidence (2 references)

PMID:35163840 SUPPORT Human Clinical

"IRIDA patients had significantly lower TSAT/hepcidin ratios compared to IDA controls, median 0.6%/nM (interquartile range, IQR, 0.4-1.1%/nM) and 16.7%/nM (IQR, 12.0-24.0%/nM), respectively."

The separation the threshold sits inside, with both group distributions given rather than only the cut-off.

PMID:35163840 SUPPORT Human Clinical

"The TSAT/hepcidin ratio shows excellent performance in discriminating IRIDA from TMPRSS6-unrelated IDA early in the diagnostic work-up of IDA provided that recent iron therapy and moderate-to-severe inflammation are absent."

Graded PARTIAL because the sentence carries its own conditions: the performance claim holds only under the two exclusions curated above, which is why they are inclusion criteria of the rule rather than footnotes to it.

Notes: The 5.6 %/nM threshold is method-bound. Hepcidin was measured by standardised isotope dilution mass spectrometry, and routine hepcidin immunoassays are not calibrated to it, so the numeric cut-off cannot be carried to another laboratory without cross-calibration. Applying it to an uncalibrated immunoassay result would be a units error dressed as a diagnosis.

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Recessive transmission was inferred in the defining study from unaffected parents of affected sibling pairs, with consanguinity in one of the five multiplex kindreds, and biallelic TMPRSS6 variants were identified where phase could be determined. Later reviews treat the disease as recessive without qualification. One caveat is worth recording because it recurs in variant interpretation. In one of the original kindreds only a single paternal allele was found; the authors did not exclude a second lesion of a class their sequencing could not see, such as a large deletion. A patient with a convincing IRIDA phenotype and one apparent TMPRSS6 allele is therefore not evidence against the recessive model. A later registry series takes this further and reports monoallelic patients as a recognised group rather than as unresolved cases: they present later in life with a milder microcytic anaemia than biallelic patients, who typically present in childhood. The disease is still described as autosomal recessive, and this entry keeps that classification, but the monoallelic observation is recorded here because it bears directly on whether a single pathogenic allele in a symptomatic adult should be reported.

Autosomal recessive inheritance

Show evidence (4 references)

PMID:18408718 SUPPORT Human Clinical

"In all five families, recessive transmission was suggested by the absence of the phenotype in the parents of affected sibling pairs; one kindred was also notable for parental consanguinity"

States the segregation basis for recessive inheritance in the defining cohort.

PMID:18408718 SUPPORT Human Clinical

"In the fourth family, we found a mutation only on the paternal allele; however, we did not exclude the presence of other types of mutations, such as large deletions, that would not be detectable by sequencing."

Graded PARTIAL because it is the one kindred where biallelic status was not demonstrated; it supports the recessive model only under the authors' stated assumption about undetected alleles.

PMID:23729726 SUPPORT Human Clinical

"Iron refractory iron deficiency anemia is a hereditary recessive anemia due to a defect in the TMPRSS6 gene encoding Matriptase-2."

An independent review restating the recessive inheritance of the entity.

+ 1 more reference

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Discussions and Knowledge Gaps

3

Is matriptase-2's suppression of hepcidin a proteolytic event at all, and if not, what does that mean for interpreting a patient's missense variant?

KNOWLEDGE GAP OPEN irida_two_mechanisms_one_gene

Attached to

pathophysiology#Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin pathophysiology#Failure to Suppress Hepcidin Transcription in Iron Deficiency

Two papers published months apart in 2008 give different answers, and this entry curates them as parallel arms rather than resolving a question it has no basis to resolve. The haemojuvelin account is enzymatic and extracellular: matriptase-2 cleaves membrane haemojuvelin, removing a BMP co-receptor that drives HAMP transcription. The promoter account is not enzymatic at all - the mouse work reports that the cytoplasmic domain mediates Hamp suppression through proximal promoter elements, which is not something an ectodomain protease activity explains. A third result reframes the question rather than settling it between those two. Dissecting the proteolytic and non-proteolytic contributions in mice, with a protease-dead full-length allele and a truncation lacking the catalytic domain, found that the catalytic domain was required to suppress hepcidin - but its proteolytic activity was not. Binding, not cutting: the ectodomain engaging haemojuvelin, Alk3, ActRIIA and Hfe. A disease-causing allele in that same work could still be activated and still failed to suppress hepcidin, and what it had lost was its interaction with those partners. So the live question is no longer only *which domain*, it is *whether the disease is a loss of proteolysis at all*. Note the entry keeps the cleavage node rather than deleting it: matriptase-2 does cleave haemojuvelin, the reaction is real, and human disease alleles impair it. What is now in doubt is whether that cleavage is what the hepcidin suppression runs through. The reason this is not academic, and it has sharpened. Every functional assay used to classify a novel TMPRSS6 variant reads out cleavage. If suppression is a binding function, a variant that cleaves normally in an assay may still be pathogenic through lost partner interaction, and a cleavage-normal result is not reassurance. The same paper says so in its own conclusion - that proteolytic activity is not an appropriate target for modulating MT2 therapeutically - which is the drug-discovery version of the same point.

Proposed experiments

Separation-of-function TMPRSS6 alleles in hepatocytes

exp_irida_domain_separation

Express catalytically dead and cytoplasmic-domain-deleted TMPRSS6 at endogenous levels in primary or iPSC-derived human hepatocytes and measure HAMP transcription and membrane haemojuvelin independently. If catalytic inactivation alone reproduces the full loss of Hamp suppression, the cytoplasmic-domain effect is downstream or dispensable.

Would support

pathophysiology#Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin

Would refute

pathophysiology#Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin

Supporting outcome

A catalytically dead allele fails to suppress HAMP and fails to clear membrane haemojuvelin, while the cytoplasmic-domain deletion behaves like wild type.

Refuting outcome

A catalytically dead allele still suppresses HAMP normally, placing the operative activity outside the protease domain.

Partner-binding assay alongside cleavage for a panel of TMPRSS6 variants

exp_irida_binding_versus_cleavage_variant_panel

Assay a panel of reported IRIDA missense variants for both haemojuvelin cleavage and ectodomain binding to haemojuvelin, ALK3, ACTRIIA and HFE, and test which readout better predicts hepcidin suppression. If binding predicts and cleavage does not, the standard functional assay used in variant classification is measuring the wrong thing.

Would support

pathophysiology#Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin

Would refute

pathophysiology#Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin

Supporting outcome

Cleavage capacity predicts hepcidin suppression across the panel at least as well as partner binding does.

Refuting outcome

Variants that cleave haemojuvelin normally but bind partners poorly fail to suppress hepcidin, showing the disease runs through binding rather than proteolysis.

Show evidence (3 references)

PMID:32384154 SUPPORT Model Organism

"Studies of the protease-dead full-length Mt2 (Mt2S762A) and the truncated Mt2 that lacks the catalytic domain (Mt2mask) indicate that the catalytic domain, but not its proteolytic activity, was required for Mt2 to suppress hepcidin expression."

The separation-of-function result that reframes the question: domain required, activity not.

PMID:32384154 SUPPORT Model Organism

"Coimmunoprecipitation analysis revealed that Mt2I286F, but not Mt2S762A, had reduced interactions with Hjv, ActRIIA, and Hfe."

Ties a disease-causing allele's failure to lost partner binding rather than to lost catalysis, which is what makes the variant-interpretation point concrete rather than theoretical.

PMID:32384154 SUPPORT Model Organism

"these observations support the idea that the substrate interaction with Mt2 plays a determinant role and suggest that the proteolytic activity is not an appropriate target to modulate the function of MT2 for clinical applications"

The authors' own conclusion, including its therapeutic corollary.

Can the diagnostic hepcidin measurement be interpreted across laboratories, and what is the decision rule?

KNOWLEDGE GAP OPEN irida_hepcidin_assay_standardisation

Attached to

biochemical#Serum hepcidin phenotypes#Hepcidin Not Suppressed Despite Iron Deficiency

A decision rule exists, it performs extremely well, and it is not yet safe to treat as a general-purpose test. Those three things are all true and the entry curates the rule in `definitions` rather than in prose so the caveats travel with it. The rule is the transferrin-saturation-to-hepcidin ratio, below 5.6 %/nM, and in its derivation study it separated 20 IRIDA patients from 39 iron-deficient controls with an area under the curve of 1.000 - perfect separation, sensitivity and specificity both 100%. That is a stronger result than this differential usually gets. What is not settled is whether the number transfers. Three things about the derivation constrain it. Hepcidin was measured by standardised isotope-dilution mass spectrometry, and the cut-off is expressed in nM against that method; routine hepcidin immunoassays are not calibrated to it, so 5.6 %/nM is not portable to another laboratory's units without recalibration. The controls were selected to exclude recent iron therapy and CRP of 10.0 mg/L or above, which removes the two commonest confounders in exactly the population where the test would be used. And with an AUC of 1.000 in 59 people, the confidence intervals are what carry the information, not the point estimate: the authors report them as 84-100% and 91-100% and say the observations warrant further exploration in a broader population. This is why `reference_ranges` on the hepcidin biomarker is still empty. A single-analyte interval is the wrong object here - the informative quantity is the ratio, and the ratio's threshold is method-bound.

Proposed experiments

External validation of the TSAT/hepcidin ratio in an unselected population

exp_irida_hepcidin_ratio_external_validation

Apply the 5.6 %/nM threshold prospectively in consecutive patients presenting with iron deficiency anaemia in routine practice - without excluding recent iron therapy or mild inflammation - with TMPRSS6 sequencing as the reference standard, and report the operating characteristics alongside a cross-calibration of the local hepcidin assay against isotope-dilution mass spectrometry.

Would support

definitions#Transferrin saturation to hepcidin ratio

Would refute

definitions#Transferrin saturation to hepcidin ratio

Supporting outcome

The published threshold retains a useful positive predictive value in consecutive unselected patients after assay cross-calibration.

Refuting outcome

Discrimination degrades substantially once recent iron therapy and mild inflammation are no longer exclusions, or the threshold shifts materially between hepcidin methods.

Does matriptase-2 cleave its partners in the liver the way it does in cultured hepatoma cells, and which system should a variant's functional assay be run in?

HUMAN MODEL MISMATCH OPEN irida_neogenin_liver_versus_cell_line

Attached to

pathophysiology#Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin

Nearly all the functional evidence for this disease is transfected-cell biochemistry, and there is now a direct demonstration that at least one of those cell-line results does not hold in vivo. Matriptase-2 cleaves neogenin and sharply reduces neogenin levels in cultured hepatoma cells. In mouse liver it does the opposite - it stabilises neogenin - and matriptase-2's suppression of hepcidin turns out to require neogenin to be present. The same protease, the same partner, opposite directions in the two systems. That is a `HUMAN_MODEL_MISMATCH` rather than a `KNOWLEDGE_GAP` in the strict sense used here: the evidence exists and is good, and what is uncertain is which system's answer describes a patient's hepatocyte. The practical stake is variant interpretation. A novel TMPRSS6 missense variant is currently assessed by exactly the transfected-cell cleavage assay whose fidelity this result puts in question, and a variant that cleaves normally in a hepatoma line is not thereby shown to be benign. Note the mismatch here is model-to-model, mouse liver against human cell line, with the human hepatocyte unobserved in both. That makes it a weaker claim about human biology than the label might suggest, and a stronger one about not trusting the cell line alone.

Proposed experiments

Same-allele comparison across hepatoma line, primary hepatocyte and liver

exp_irida_cleavage_assay_system_comparison

Run the same panel of IRIDA missense alleles through the haemojuvelin and neogenin cleavage assays in a hepatoma line, in primary or iPSC-derived human hepatocytes, and in humanised mouse liver, and compare the rank order of functional impairment across the three systems. Concordant rank order would license continued use of the cheap assay; discordance would say which alleles have been misclassified.

Would support

pathophysiology#Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin

Would refute

pathophysiology#Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin

Supporting outcome

Allele impairment ranks the same way in the hepatoma line as in hepatocytes and liver, so the cell-line assay is a valid surrogate.

Refuting outcome

Alleles that look severely impaired in the hepatoma line behave normally in hepatocytes or liver, or the reverse.

Show evidence (2 references)

PMID:41534828 SUPPORT Model Organism

"In contrast to the observations that Mt2 cleaves Neo1 and markedly reduces Neo1 levels in cultured hepatoma cells, we found that Mt2 stabilizes Neo1 in murine liver."

The mismatch itself, stated by the authors as an explicit contrast between the cultured cell line and the intact liver.

PMID:41534828 SUPPORT Model Organism

"Studies in mice suggest that Mt2 suppression of hepcidin relies on the presence of Neo1."

Establishes that neogenin is required for the suppression, which is why the discrepant neogenin result bears on the disease mechanism rather than being an incidental cell-biology difference.

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Pathophysiology

8

Biallelic TMPRSS6 Loss of Function

Germline TMPRSS6 variants - frameshift, splice-junction, nonsense and missense - on both alleles. In the defining cohort every variant lay distal to exon 8, in the region encoding the conserved ectodomain modules and especially the trypsin-like serine protease domain, and homozygous frameshifts predicted to disrupt only the catalytic domain were sufficient to cause disease. The reported allelic spectrum has since broadened across the whole large ectodomain rather than concentrating in the catalytic domain, which is why a novel missense variant outside the protease domain cannot be dismissed on position alone.

hepatocyte CL:0000182

TMPRSS6 hgnc:16517

matriptase-2 serine protease activity GO:0004252 ⇓ LOSS OF FUNCTION

liver UBERON:0002107

Downstream

Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin

Failure to Suppress Hepcidin Transcription in Iron Deficiency

Show evidence (3 references)

PMID:18408718 SUPPORT Human Clinical

"Here, we show that iron deficiency anemia refractory to oral iron therapy can be caused by germline mutations in TMPRSS6, which encodes a type II transmembrane serine protease produced by the liver that regulates the expression of the systemic iron regulatory hormone hepcidin."

The gene-disease assertion, the protein class, and the hepatic site of expression in one sentence.

PMID:18408718 SUPPORT Human Clinical

"Nonetheless, the finding of individuals with IRIDA harboring homozygous frameshift mutations predicted to disrupt only the catalytic domain suggests that this portion of the molecule is important for iron homeostasis."

Supports catalytic-domain loss as sufficient for the phenotype, which is what makes the protease activity the curated molecular function here.

PMID:23729726 SUPPORT Human Clinical

"To date, 40 different Matriptase-2 mutations have been reported, affecting all the functional domains of the large ectodomain of the protein."

Records that the allelic spectrum spans the whole ectodomain rather than only the protease domain.

Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin

Matriptase-2 cleaves haemojuvelin at the plasma membrane. Haemojuvelin is a BMP co-receptor that drives HAMP transcription, so removing it from the hepatocyte surface lowers hepcidin; failing to remove it keeps hepcidin up. Graded PROVISIONAL, and the reason is specific rather than generic caution. The supporting evidence is strong for the reaction and weak for the location. Eight IRIDA missense alleles were assayed and seven of them impair matriptase-2 autoactivation, reduce membrane haemojuvelin cleavage, and fail to inhibit haemojuvelin-dependent hepcidin activation - a genotype-activity correspondence across human disease alleles, not a single anecdote. But every one of those measurements is in transfected cells, none is in a patient hepatocyte, and in vivo mouse work finds the liver behaving differently from hepatoma cells for an adjacent substrate. The sharper problem is that in vivo dissection has since shown the catalytic domain to be required for hepcidin suppression while its proteolytic activity is not. The cleavage reaction is real and human disease alleles impair it; what is in doubt is whether the suppression runs through it. This node is retained rather than deleted for that reason, and the discussions carry the argument.

hepatocyte CL:0000182

BMP signaling through membrane hemojuvelin GO:0030509 ↑ INCREASED

Experimental models

Matriptase-2 hemojuvelin cleavage assay in transfected cells CELL LINE Demonstrates the proposed enzymatic step and shows it is graded by genotype: absent for the mouse truncation, partial for the human missense allele.

Downstream

Inappropriately Elevated Circulating Hepcidin

Show evidence (3 references)

PMID:18976966 SUPPORT In Vitro

"Matriptase-2 cleaves hemojuvelin (HJV), a regulator of hepcidin, on plasma membrane; matriptase-2(MASK) shows no cleavage activity and the human mutant only partial cleavage capacity."

Establishes the cleavage reaction and shows it is lost by the mouse mutant and reduced by a human disease allele.

PMID:23729726 SUPPORT In Vitro

"In vitro experiments on transfected cells suggest that Matriptase-2 cleaves Hemojuvelin, a major regulator of hepcidin expression and that this function is altered in this genetic form of anemia."

Graded PARTIAL because the review itself frames the cleavage mechanism as what transfected-cell experiments suggest, which is the hedge this node's PROVISIONAL grade records.

PMID:25156943 SUPPORT In Vitro

"All but the p.T287N variant impair matriptase-2 autoproteotylic activation, decrease the ability to cleave membrane HJV and inhibit the HJV-dependent hepcidin activation."

Extends the cleavage mechanism from one allele to a series of human IRIDA missense variants, with an explicit exception. The quoted sentence contains the source's own spelling, "autoproteotylic". It is a typographical error for "autoproteolytic" and it is reproduced exactly because the cache is the authority for a snippet. Do not correct it - a tidied quote fails reference validation, which is how this one was first noticed.

Failure to Suppress Hepcidin Transcription in Iron Deficiency

The functional lesion stated at the level the disease is actually defined by: TMPRSS6 is the component that lets the liver register iron deficiency and shut off HAMP transcription. The mask mouse maps this directly - a splicing defect in Tmprss6 produces microcytic anaemia through reduced dietary iron absorption caused by high hepcidin. Note that the mouse work locates the Hamp-suppressing activity in the TMPRSS6 cytoplasmic domain acting on proximal promoter elements. That is a different molecular route from ectodomain cleavage of haemojuvelin, and the two are curated as parallel arms rather than as one chain.

hepatocyte CL:0000182

transcriptional repression of the hepcidin gene HAMP GO:0000122 ↓ DECREASED

Animal models

mask mouse (Tmprss6 splice-site mutant) Mouse recapitulates The mouse reproduces the core lesion - Tmprss6 loss, high hepcidin, reduced dietary iron absorption, microcytic anaemia - and is the system in which the Hamp-promoter mechanism was demonstrated.

Downstream

Inappropriately Elevated Circulating Hepcidin

Show evidence (2 references)

PMID:18451267 SUPPORT Model Organism

"TMPRSS6 is an essential component of a pathway that detects iron deficiency and blocks Hamp transcription, permitting enhanced dietary iron absorption."

The mouse study's summary claim, and the clearest statement of what the lost function is.

PMID:18451267 SUPPORT Model Organism

"Overexpression of normal TMPRSS6 protein suppresses activation of the Hamp promoter, and the TMPRSS6 cytoplasmic domain mediates Hamp suppression via proximal promoter element(s)."

Locates the suppressing activity in the cytoplasmic domain - the claim that makes this a separate arm from ectodomain haemojuvelin cleavage.

Inappropriately Elevated Circulating Hepcidin

The pivotal node, and the one that makes the disease diagnosable. Hepcidin is normally undetectable in iron deficiency. In IRIDA it is within or above the normal range in a patient who is iron deficient - not high in absolute terms so much as high for the iron status, which is why a hepcidin value read without the transferrin saturation beside it is uninformative.

systemic iron homeostasis GO:0060586

Downstream

Impaired Duodenal Iron Absorption

Macrophage Iron Sequestration

Show evidence (4 references)

PMID:18408718 SUPPORT Human Clinical

"Although urinary hepcidin levels are typically undetectable in individuals with iron deficiency"

The comparator that makes the IRIDA measurement abnormal; quoted separately from the finding itself because it is a statement about ordinary iron deficiency, not about IRIDA.

PMID:18408718 SUPPORT Human Clinical

"in the five affected individuals from three IRIDA kindreds we examined, urinary hepcidin/creatinine ratios were either within or above the normal range"

The measurement in patients, in five individuals across three kindreds.

PMID:23729726 SUPPORT Human Clinical

"In contrast to the low/undetectable hepcidin levels observed in acquired iron deficiency, in patients with Matriptase-2 deficiency, serum hepcidin is inappropriately high for the low iron status"

States the finding as inappropriateness for the iron status rather than as an absolute elevation, which is how the node is worded.

+ 1 more reference

Impaired Duodenal Iron Absorption

Hepcidin restricts iron entry into plasma at the basolateral surface of the duodenal enterocyte. With hepcidin high, dietary iron - whether from food or from an oral supplement - is not delivered to the circulation, which is the direct explanation for refractoriness to oral iron.

duodenal enterocyte CL:0000584

intestinal iron absorption GO:0050892 ↓ DECREASED iron export across the basolateral enterocyte membrane GO:0034755 ↓ DECREASED

duodenum UBERON:0002114

Downstream

Systemic Iron Restriction

Show evidence (4 references)

PMID:18451267 SUPPORT Model Organism

"Hepcidin, a liver-derived protein that restricts enteric iron absorption, is the key regulator of body iron content."

The general mechanism by which raised hepcidin blocks absorption.

PMID:18451267 SUPPORT Model Organism

"The mask phenotype results from reduced absorption of dietary iron caused by high levels of hepcidin and is due to a splicing defect in the transmembrane serine protease 6 gene Tmprss6."

Demonstrates the hepcidin-to-malabsorption step in the Tmprss6-deficient animal.

PMID:18408718 SUPPORT Human Clinical

"it may explain the failure to absorb dietary iron despite systemic iron deficiency"

The authors' own reading of what raised hepcidin explains in their patients.

+ 1 more reference

Macrophage Iron Sequestration

The second, less obvious limb, and the one that explains why parenteral iron is not a clean rescue. Hepcidin also blocks iron release from macrophages. Parenteral iron formulations are taken up by the reticuloendothelial system and must be re-exported before erythroid precursors can use them, so a hepcidin block downstream of the injection limits the response even when the gut has been bypassed entirely.

macrophage CL:0000235

macrophage iron release into plasma GO:0034755 ↓ DECREASED

Downstream

Systemic Iron Restriction

Show evidence (4 references)

PMID:18408718 SUPPORT Human Clinical

"hepcidin, a hormone produced by the liver that regulates intestinal iron absorption and macrophage iron release"

Establishes macrophage iron release as the second hepcidin-regulated step.

PMID:18408718 SUPPORT Human Clinical

"as well as the coexistent failure to respond to parenteral iron administered as iron-dextran, which must be processed and exported by macrophages before utilization for erythropoiesis"

Ties the macrophage block specifically to the incomplete parenteral-iron response, which is the clinically visible consequence of this node.

PMID:35163840 SUPPORT Human Clinical

"Since hepcidin impairs intestinal iron absorption and recycling by inhibiting ferroportin-mediated iron export from enterocytes and macrophages"

The macrophage half of the same ferroportin statement, which is what makes recycling as well as absorption hepcidin-dependent.

+ 1 more reference

Systemic Iron Restriction

Both limbs converge on a reduced supply of transferrin-bound iron to the marrow. The biochemical shadow of this node is the low transferrin saturation that, together with a non-suppressed hepcidin, defines the diagnostic pattern.

systemic iron homeostasis GO:0060586 ↓ DECREASED

Downstream

Iron-Restricted Erythropoiesis

Show evidence (1 reference)

PMID:23729726 SUPPORT Human Clinical

"Hallmarks of this disease are microcytic hypochromic anemia, low transferrin saturation and normal/high serum hepcidin values."

The three-part laboratory signature, of which low transferrin saturation is this node's readout.

Iron-Restricted Erythropoiesis

Erythroid precursors deprived of iron undergo extra divisions and produce small, poorly haemoglobinised red cells. The marrow itself is not the diseased compartment - it is a normal marrow starved of substrate - which is why the anaemia is typically moderate and non-progressive rather than transfusion-dependent.

erythroid progenitor cell CL:0000038

bone marrow UBERON:0002371

Show evidence (2 references)

PMID:23729726 SUPPORT Human Clinical

"Hallmarks of this disease are microcytic hypochromic anemia, low transferrin saturation and normal/high serum hepcidin values."

The erythroid output of the restricted supply - microcytic, hypochromic red cells.

PMID:18451267 SUPPORT Model Organism

"We describe mask: a recessive, chemically induced mutant mouse phenotype, characterized by progressive loss of body (but not facial) hair and microcytic anemia."

The same erythroid consequence in the Tmprss6-deficient mouse. Graded MODEL_ORGANISM and kept distinct from the human evidence above.

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Pathograph

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Phenotypes

8

Blood 4

Hypochromic Microcytic Anemia OBLIGATE HP:0004840

Kept at OBLIGATE for the anaemia, which no report contradicts, but the *microcytosis* is not universal: a proband in one of six Saudi IRIDA families presented with normocytic anaemia and a normal MCV. That is curated on the separate MCV phenotype below, which is banded VERY_FREQUENT rather than OBLIGATE for exactly this reason. Splitting the anaemia from its red-cell indices is what lets the entry hold both facts.

Show evidence (2 references)

PMID:23729726 SUPPORT Human Clinical

"Hallmarks of this disease are microcytic hypochromic anemia, low transferrin saturation and normal/high serum hepcidin values."

Names the anaemia as a hallmark of the disease.

PMID:23729726 SUPPORT Human Clinical

"The anemia appears in the post-natal period, although in some cases it is only diagnosed in adulthood."

Supports the onset statement and the diagnostic-delay note in the description.

Very Low Mean Corpuscular Volume VERY_FREQUENT Decreased mean corpuscular volume HP:0025066

Show evidence (2 references)

PMID:18408718 SUPPORT Human Clinical

"a congenital hypochromic, microcytic anemia, a very low mean corpuscular erythrocyte volume, a low transferrin saturation"

Lists a very low MCV among the key features defining the phenotype.

PMID:36261087 REFUTE Human Clinical

"The proband of family 6 presented numerous hematological abnormalities upon initial consultation, including normocytic anemia accompanied by low Hb, normal MCV, low serum iron, low serum ferritin, and normal TIBC."

Graded REFUTE against microcytosis being universal. One proband of six families had a normal MCV, which is why this phenotype is VERY_FREQUENT rather than OBLIGATE. Note this patient also had *low* ferritin, so the ferritin phenotype above is likewise not universal.

Refractoriness to Oral Iron VERY_FREQUENT Iron deficiency anemia HP:0001891

The HP binding is deliberately the general term HP:0001891 "Iron deficiency anemia". HPO has no term for refractoriness to a specific therapy, so the treatment-response part of this phenotype lives in preferred_term and the description rather than in the ontology binding. Do not substitute a narrower-sounding term that does not mean this. Note the tension this phenotype now carries and should keep carrying: the disease is *named* for oral-iron refractoriness, and a genotype-confirmed kindred responds to oral iron. Both are true. Resolving it by dropping either the name or the exception would lose information.

Show evidence (3 references)

PMID:18408718 SUPPORT Human Clinical

"abnormal iron absorption characterized by no hematological improvement following treatment with oral iron"

Oral-iron refractoriness as one of the defining key features of the phenotype.

PMID:25064705 SUPPORT Human Clinical

"multiple family members are affected with iron deficiency anemia that is unresponsive to oral iron supplementation and only partially responsive to parenteral iron therapy"

Independent restatement, and it also records the partial parenteral response curated as its own phenotype below.

PMID:23319530 REFUTE Human Clinical

"Thus, the phenotype associated with the unique combination of mutations uncovered in both patients expands the spectrum of disease associated with TMPRSS6 mutations to include iron deficiency anemia that is accompanied by hyperferritinemia at initial presentation and is responsive to continued..."

Graded REFUTE against the claim that oral-iron refractoriness is obligate. This is the counterexample that sets the frequency band, and it is quoted from the authors' own conclusion rather than inferred from their case description.

Incomplete Response to Parenteral Iron VERY_FREQUENT Iron deficiency anemia HP:0001891

Show evidence (2 references)

PMID:23729726 SUPPORT Human Clinical

"The disease is refractory to oral iron treatment but shows a slow response to intravenous iron injections and partial correction of the anemia."

States both the partial nature and the slowness of the parenteral response.

PMID:18408718 SUPPORT Human Clinical

"abnormal iron utilization characterized by a sluggish, incomplete response to parenteral iron"

The same finding in the defining cohort, described as a utilisation rather than an absorption defect.

Metabolism 1

Hyperferritinemia at Presentation VERY_RARE Increased circulating ferritin concentration HP:0003281

Show evidence (2 references)

PMID:23319530 SUPPORT Human Clinical

"We report a French-Canadian kindred in which 2 siblings presented in early childhood with severe microcytic anemia, hypoferremia, and hyperferritinemia. Both children have been successfully treated solely with low-dose oral iron since diagnosis."

The presentation and, in the same sentence, the treatment response that makes this kindred doubly exceptional.

PMID:23319530 SUPPORT Human Clinical

"Whole exome sequencing identified in both patients compound heterozygous mutations of TMPRSS6 leading to p.G442R and p.E522K, 2 mutations previously reported to cause classic IRIDA"

Establishes that the atypical presentation is not explained by atypical alleles - both variants had already been reported in classic IRIDA.

Other 3

Low Transferrin Saturation VERY_FREQUENT Decreased transferrin saturation HP:0012464

Show evidence (2 references)

PMID:23729726 SUPPORT Human Clinical

"Hallmarks of this disease are microcytic hypochromic anemia, low transferrin saturation and normal/high serum hepcidin values."

Names low transferrin saturation as a hallmark.

PMID:18408718 SUPPORT Human Clinical

"In all cases, Hb, MCV and transferrin saturation were below the respective reference ranges provided by the referring hospital laboratory."

Confirms the finding held across every index case in the defining cohort.

Hepcidin Not Suppressed Despite Iron Deficiency VERY_FREQUENT Elevated circulating hepcidin concentration HP:0031877

Show evidence (2 references)

PMID:18408718 SUPPORT Human Clinical

"The finding of inappropriately elevated urinary hepcidin levels in individuals with IRIDA provides insight into the pathophysiology of the disorder"

The primary measurement of non-suppressed hepcidin in patients.

PMID:23729726 SUPPORT Human Clinical

"In contrast to the low/undetectable hepcidin levels observed in acquired iron deficiency, in patients with Matriptase-2 deficiency, serum hepcidin is inappropriately high for the low iron status"

States the contrast with acquired iron deficiency that gives the finding its discriminating value.

Serum Ferritin Inappropriately Preserved VERY_FREQUENT Abnormal circulating ferritin concentration HP:0040133

Bound to the general term HP:0040133 "Abnormal circulating ferritin concentration" rather than to the increased or decreased child terms, and the choice is deliberate. The finding is neither: it is a value that would be unremarkable in isolation and is abnormal only relative to the iron status. This is the same ontology gap as the hepcidin binding in this entry - HPO represents direction of change but not inappropriateness for a physiological context - and both are recorded in `notes` rather than papered over with a child term that asserts a direction the patients do not reliably show.

Show evidence (2 references)

PMID:35163840 SUPPORT Human Clinical

"In the IRIDA group, MCV levels were significantly lower and ferritin levels significantly higher in comparison with the IDA group (p = 0.01 and p < 0.001)."

The head-to-head comparison against iron-deficient controls, with both directions and both p values.

PMID:35163840 SUPPORT Human Clinical

"develop microcytic anemia with remarkably low transferrin saturation (TSAT), low-normal ferritin levels, and a poor response to oral iron treatment"

States the expected ferritin range in IRIDA alongside the other two elements of the laboratory signature.

🧬

Genetic Associations

1

TMPRSS6

Gene: TMPRSS6 hgnc:16517 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (5 references)

PMID:18408718 SUPPORT Human Clinical

"Affected individuals harbored frame-shift mutations, splice junction mutations or missense mutations altering residues conserved"

The classes of variant found, supporting the loss-of-function mechanism.

PMID:18408718 SUPPORT Human Clinical

"None of the disease-associated variants were present in the NCBI and Ensembl SNP databases or in 100 control chromosomes"

Population-absence evidence for pathogenicity of the reported alleles.

PMID:25064705 SUPPORT Human Clinical

"The discovery that many of these cases harbor mutations in the TMPRSS6 gene led to the recognition that they represent a single clinical entity: iron-refractory iron deficiency anemia (IRIDA)."

Independent statement that TMPRSS6 genotype is what delimits the entity.

+ 2 more references

🗃️

External Assertions

2

OMIM iron-refractory iron deficiency anemia record

OMIM disease record OMIM:206200

The OMIM entry for IRIDA, cross-referenced from MONDO:0008788.

Orphanet iron-refractory iron deficiency anemia record

Orphanet disease record ORPHA:209981

The Orphanet entry for IRIDA. No `references_cache/ORPHA_209981.md` exists and one could not be generated - `just fetch-reference ORPHA:209981` reports "No source found for reference type", because ORPHA records come from the structured-source builder rather than the reference fetcher, and that builder needs the Orphadata bulk XML whose pinned checksum is currently stale (dismech#9897). Recorded here as an identifier assertion rather than cited as evidence.

💊

Medical Actions

3

Parenteral Iron

Action: Pharmacotherapy NCIT:C15986

Agent: iron CHEBI:29033

The mainstay of treatment. It bypasses the blocked duodenal step but not the macrophage one, so the response is slow and the correction partial rather than complete.

Mechanism Target:

BYPASSES Impaired Duodenal Iron Absorption — Delivering iron intravenously circumvents the enterocyte export block entirely. It does nothing about the hepcidin elevation that caused it, which is why this is curated as BYPASSES rather than INHIBITS or RESTORES.

Show evidence (1 reference)

PMID:23729726 SUPPORT Human Clinical

"The disease is refractory to oral iron treatment but shows a slow response to intravenous iron injections and partial correction of the anemia."

Supports parenteral iron as effective where oral iron is not, and records that the correction is partial.

Show evidence (1 reference)

PMID:23729726 SUPPORT Human Clinical

"The current treatment of iron refractory iron deficiency anemia is based on parenteral iron administration"

Names parenteral iron as the current standard of care.

Oral Iron

Action: Pharmacotherapy NCIT:C15986

Agent: iron CHEBI:29033

Curated because it is what patients are given for years before the diagnosis is made, not because it works. It does not.

Show evidence (2 references)

PMID:18408718 REFUTE Human Clinical

"abnormal iron absorption characterized by no hematological improvement following treatment with oral iron"

Graded REFUTE against the claim that oral iron treats this disease. The quoted finding is a negative therapeutic result and is the reason the entity has "refractory" in its name.

PMID:30594846 SUPPORT Human Clinical

"We prospectively evaluated our IRIDA cohort (n = 7) with oral iron and vitamin c dose over a period of 10 weeks and noted complete response in majority (6/7 = 86%) with >2 g/dL rise in Hb along with significant improvement of other iron related indices."

Points the other way from the item above and is graded PARTIAL rather than SUPPORT for two reasons stated by the source itself. The cohort is seven children, uncontrolled and unblinded; and the paper's own title describes them as having the IRIDA *phenotype*, not confirmed biallelic TMPRSS6 genotype, so some may have had oral-iron-responsive iron deficiency that IRIDA was never the explanation for. This is evidence that the combination deserves a trial, not that the refractoriness claim is wrong.

Hepcidin-Lowering Therapy

Action: Pharmacotherapy NCIT:C15986

Not an available treatment. Curated as a stated therapeutic direction because the mechanism identifies the target unusually cleanly - the disease is caused by hepcidin that is too high, so an agent that lowers it would address the lesion rather than its consequence.

Show evidence (1 reference)

PMID:23729726 SUPPORT Human Clinical

"in the future, manipulation of the hepcidin pathway with the aim of suppressing it might become an alternative therapeutic approach"

Graded PARTIAL because the source states this as a prospect, not as a demonstrated therapy. No clinical trial in IRIDA is cited here, and none should be inferred from this item.

🔬

Biochemical Markers

2

Serum hepcidin (PRESENT)

Show evidence (1 reference)

PMID:23729726 SUPPORT Human Clinical

"Hallmarks of this disease are microcytic hypochromic anemia, low transferrin saturation and normal/high serum hepcidin values."

Establishes serum hepcidin as a hallmark laboratory measurement in the disease.

Transferrin saturation (PRESENT)

Show evidence (1 reference)

PMID:18408718 SUPPORT Human Clinical

"Transferrin saturation (%) was calculated by dividing the serum iron level by the total iron binding capacity and multiplying by 100."

The measurement definition used to characterise the defining cohort.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

No population prevalence estimate is published. The literature describes the entity through kindreds and case series rather than through an epidemiological denominator, and the closest quantitative anchor is the count of distinct reported TMPRSS6 alleles - forty by 2013 - which counts mutations, not patients, and is recorded here only as an order-of-magnitude indication that the reported population is small. rate_per_100000 is deliberately left empty. Deriving a rate from an allele count would be an invention.

Show evidence (1 reference)

PMID:23729726 SUPPORT Human Clinical

"To date, 40 different Matriptase-2 mutations have been reported, affecting all the functional domains of the large ectodomain of the protein."

Graded PARTIAL: it bounds the size of the reported literature but is a count of alleles rather than of patients, and is not a prevalence measurement.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from IRIDA Syndrome:

Acquired iron deficiency anemia

Overlapping Features The differential that matters, because it is overwhelmingly more common and the two overlap heavily on a full blood count and iron panel. They are not strictly indistinguishable: measured head to head, IRIDA patients had lower MCV and higher ferritin than iron-deficient controls, both significantly. But those are group differences with overlapping distributions, not a rule for an individual, and the ferritin difference points the counter-intuitive way - higher in the patient with the genetic iron-handling defect. The separating test is hepcidin, read against the transferrin saturation: suppressed in acquired deficiency, not suppressed in IRIDA. The therapeutic trial separates them too, but only after months of ineffective treatment, and a genotype-confirmed kindred responsive to oral iron shows even that is not absolute.

Distinguishing Features

Hepcidin is low or undetectable in acquired iron deficiency, but within or above the normal range in IRIDA despite an equally low transferrin saturation.
Ferritin is significantly higher in IRIDA than in acquired iron deficiency, because the iron is sequestered rather than absent - the opposite of the naive expectation.
A haematological response to oral iron argues strongly against IRIDA, but does not exclude it; a genotype-confirmed kindred has been maintained on low-dose oral iron alone.

Show evidence (1 reference)

PMID:23729726 SUPPORT Human Clinical

"In contrast to the low/undetectable hepcidin levels observed in acquired iron deficiency, in patients with Matriptase-2 deficiency, serum hepcidin is inappropriately high for the low iron status"

States the discriminating direction of the hepcidin result between the two conditions.

Thalassemia trait and other inherited microcytoses

Overlapping Features A congenital microcytic anaemia with a very low MCV in a child invites a haemoglobinopathy work-up first, and IRIDA is commonly found only after that is negative. The defining study excluded the other inherited causes of microcytosis explicitly before implicating TMPRSS6.

Distinguishing Features

Transferrin saturation is low in IRIDA and typically normal in thalassaemia trait.
Haemoglobin electrophoresis is normal in IRIDA.

Show evidence (2 references)

PMID:18408718 SUPPORT Human Clinical

"Acquired causes of iron deficiency and other inherited causes of microcytosis were rigorously excluded"

Records that the entity was delimited by exclusion of exactly this differential.

PMID:23729726 SUPPORT Human Clinical

"A challenge for the clinicians and pediatricians is the recognition of the disorder among iron deficiency and other microcytic anemias commonly found in pediatric patients."

States the recognition problem this differential describes.

🧫

Experimental Models

1

Matriptase-2 hemojuvelin cleavage assay in transfected cells CELL_LINE

Co-expression of matriptase-2 - wild type, the mask truncation, or the human disease allele R774C - with haemojuvelin in cultured cells, read out by hepcidin promoter activity and by cleavage of membrane haemojuvelin.

Pathograph links

Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin recapitulates fidelity: moderate Demonstrates the proposed enzymatic step and shows it is graded by genotype: absent for the mouse truncation, partial for the human missense allele.

Limitations: Overexpression in a heterologous cell line rather than a hepatocyte carrying the variant at its endogenous locus, so the assay establishes that the reaction can occur and is genotype-sensitive, not that it is the rate-limiting step in a patient's liver. Fidelity is graded MODERATE on that basis.

Readouts

Membrane hemojuvelin cleavage by matriptase-2 variants

Direction: DECREASED

Interpretation: Cleavage is abolished by the mask truncation and reduced by the human R774C allele relative to wild-type matriptase-2.

Show evidence (1 reference)

PMID:18976966 SUPPORT In Vitro

"matriptase-2(MASK) shows no cleavage activity and the human mutant only partial cleavage capacity"

The graded cleavage result that this readout records.

Show evidence (1 reference)

PMID:18976966 SUPPORT In Vitro

"Here we confirm the inhibitory effect of matriptase-2 on hepcidin promoter; we show that matriptase-2 lacking the serine protease domain, identified in the anemic Mask mouse (matriptase-2(MASK)), is fully inactive and that mutant R774C found in patients with genetic iron deficiency has decreased..."

Supports the assay as informative for the cleavage node, with an explicit genotype-activity relationship.

🐁

Animal Models

1

mask mouse (Tmprss6 splice-site mutant)

A chemically induced recessive mouse mutant recovered on phenotype - hair loss and microcytic anaemia - and mapped to a Tmprss6 splicing defect. It is the model that established what the human gene does, and it was published within weeks of the human gene discovery.

Species

Mouse

Genotype

Tmprss6 mask, homozygous ENU-induced splicing defect

Publication

PMID:18451267

Pathograph links

Failure to Suppress Hepcidin Transcription in Iron Deficiency recapitulates fidelity: high The mouse reproduces the core lesion - Tmprss6 loss, high hepcidin, reduced dietary iron absorption, microcytic anaemia - and is the system in which the Hamp-promoter mechanism was demonstrated.

Limitations: One phenotypic divergence is worth stating rather than glossing. The mouse is named for progressive loss of body but not facial hair, and alopecia of this kind is not a feature of human IRIDA. Whatever produces the mask coat phenotype is therefore either mouse-specific or an aspect of matriptase-2 biology that human patients do not show, and it should not be used to predict a human phenotype.

Readouts

Red cell volume and dietary iron absorption

Direction: DECREASED

Interpretation: Microcytic anaemia resulting from reduced dietary iron absorption, the mouse counterpart of the human erythroid phenotype.

Show evidence (1 reference)

PMID:18451267 SUPPORT Model Organism

"The mask phenotype results from reduced absorption of dietary iron caused by high levels of hepcidin and is due to a splicing defect in the transmembrane serine protease 6 gene Tmprss6."

Reports the measured absorption defect and its hepcidin cause in the mutant.

Show evidence (1 reference)

PMID:18451267 SUPPORT Model Organism

"TMPRSS6 is an essential component of a pathway that detects iron deficiency and blocks Hamp transcription, permitting enhanced dietary iron absorption."

Supports treating this model as informative for the hepcidin-suppression node.

{ }

Source YAML

click to show

name: IRIDA Syndrome
creation_date: "2026-08-29T11:30:00Z"
category: Mendelian
disease_term:
  preferred_term: Iron-refractory iron deficiency anemia
  term:
    id: MONDO:0008788
    label: IRIDA syndrome
description: >-
  Iron-refractory iron deficiency anaemia (IRIDA) is an autosomal recessive
  microcytic hypochromic anaemia caused by biallelic loss-of-function variants
  in TMPRSS6, which encodes the hepatocyte type II transmembrane serine protease
  matriptase-2.

  Its interest is out of proportion to its rarity, because it is the disease
  that establishes the direction of a regulatory arrow. Hepcidin restricts iron
  entry into plasma, and it is suppressed when the body is iron deficient. What
  performs that suppression was unknown until IRIDA and its mouse counterpart
  were mapped to the same gene. Matriptase-2 is the sensor arm: without it,
  hepcidin cannot be turned down, and the body responds to iron deficiency by
  behaving as though it were iron replete.

  The consequence is a diagnostically inverted picture. In ordinary iron
  deficiency, hepcidin falls to undetectable levels and oral iron works. In
  IRIDA hepcidin is normal or high while the patient is iron deficient, so the
  duodenal enterocyte cannot export absorbed iron into plasma and the macrophage
  cannot release its stores. Oral iron therefore fails, and parenteral iron -
  which bypasses the gut but is still handled by macrophages - corrects the
  anaemia only slowly and partially. The laboratory signature is the
  combination that should prompt the diagnosis: microcytosis with a very low
  MCV, low transferrin saturation, and a hepcidin level that is inappropriately
  high for the iron status rather than low.

  Two mechanistic accounts of how matriptase-2 suppresses hepcidin were
  published within months of each other in 2008 and are not the same claim. One
  locates the activity in the protease ectodomain, which cleaves membrane
  haemojuvelin and so removes a BMP co-receptor that drives HAMP transcription.
  The other locates it in the cytoplasmic domain, acting on the Hamp proximal
  promoter. The entry curates both and does not merge them; the discussion below
  says why that matters for interpreting a patient's missense variant.
parents:
- hereditary disease
- Anemia
synonyms:
- IRIDA
- iron-refractory iron deficiency anemia
- iron-refractory iron deficiency anaemia
- matriptase-2 deficiency
- TMPRSS6-related iron deficiency anemia
- anemia, hypochromic microcytic, with defect in iron metabolism
classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
    notes: >-
      A hereditary microcytic anaemia; the clinical problem is an anaemia and its
      differential diagnosis against acquired iron deficiency and thalassaemia
      trait.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian recessive disorder identified by linkage and candidate-gene
      sequencing in multiplex kindreds.
  icimd_category:
  - classification_value: iron_metabolism
    notes: >-
      ICIMD group "Disorders of iron metabolism" under category 22, disorders of
      trace elements and metals. Placed on the metabolic axis rather than treated
      as a primary bone-marrow disorder: the erythroid compartment is normal and
      is starved of substrate by a defect in systemic iron handling upstream of
      it.

      No `mechanistic_category` is assigned. That enum is a small closed set of
      protein-class nosologies (RASopathy, ciliopathy, laminopathy and so on) and
      none of them describes a hepatic protease that regulates a hormone; leaving
      it empty is the accurate answer rather than a gap.
references:
- reference: PMID:18408718
  title: "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)."
- reference: PMID:18451267
  title: "The serine protease TMPRSS6 is required to sense iron deficiency."
- reference: PMID:18976966
  title: "The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin."
- reference: PMID:23729726
  title: "Iron refractory iron deficiency anemia."
- reference: PMID:25064705
  title: "Iron-refractory iron deficiency anemia (IRIDA)."
- reference: PMID:25156943
  title: "Functional and clinical impact of novel TMPRSS6 variants in iron-refractory iron-deficiency anemia patients and genotype-phenotype studies."
- reference: PMID:35163840
  title: "Transferrin Saturation/Hepcidin Ratio Discriminates TMPRSS6-Related Iron Refractory Iron Deficiency Anemia from Patients with Multi-Causal Iron Deficiency Anemia."
- reference: PMID:42053460
  title: "A Phase 1 Randomized, Double-Blind, Placebo-Controlled Single and Multiple Ascending Dose Study of DISC-3405, a Novel Recombinant Humanized Monoclonal Antibody Targeting TMPRSS6, in Adult Healthy Volunteers."
- reference: PMID:41534828
  title: "Matriptase-2-mediated suppression of hepatic hepcidin expression in mice requires hepatocyte neogenin."
- reference: PMID:30594846
  title: "Favourable improvement in haematological parameters in response to oral iron and vitamin C combination in children with Iron Refractory Iron Deficiency Anemia (IRIDA) phenotype."
- reference: PMID:32384154
  title: "The ectodomain of matriptase-2 plays an important nonproteolytic role in suppressing hepcidin expression in mice."
- reference: PMID:23319530
  title: "Iron refractory iron deficiency anemia: presentation with hyperferritinemia and response to oral iron therapy."
- reference: PMID:36261087
  title: "TMPRSS6 gene mutations in six Saudi families with iron refractory iron deficiency anemia."
external_assertions:
- name: OMIM iron-refractory iron deficiency anemia record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:206200
  url: https://omim.org/entry/206200
  description: >-
    The OMIM entry for IRIDA, cross-referenced from MONDO:0008788.
- name: Orphanet iron-refractory iron deficiency anemia record
  source: Orphanet
  assertion_type: disease_record
  external_id: ORPHA:209981
  url: https://www.orpha.net/en/disease/detail/209981
  description: >-
    The Orphanet entry for IRIDA. No `references_cache/ORPHA_209981.md` exists and
    one could not be generated - `just fetch-reference ORPHA:209981` reports "No
    source found for reference type", because ORPHA records come from the
    structured-source builder rather than the reference fetcher, and that builder
    needs the Orphadata bulk XML whose pinned checksum is currently stale
    (dismech#9897). Recorded here as an identifier assertion rather than cited as
    evidence.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Recessive transmission was inferred in the defining study from unaffected
    parents of affected sibling pairs, with consanguinity in one of the five
    multiplex kindreds, and biallelic TMPRSS6 variants were identified where
    phase could be determined. Later reviews treat the disease as recessive
    without qualification.

    One caveat is worth recording because it recurs in variant interpretation.
    In one of the original kindreds only a single paternal allele was found; the
    authors did not exclude a second lesion of a class their sequencing could
    not see, such as a large deletion. A patient with a convincing IRIDA
    phenotype and one apparent TMPRSS6 allele is therefore not evidence against
    the recessive model.

    A later registry series takes this further and reports monoallelic patients
    as a recognised group rather than as unresolved cases: they present later in
    life with a milder microcytic anaemia than biallelic patients, who typically
    present in childhood. The disease is still described as autosomal recessive,
    and this entry keeps that classification, but the monoallelic observation is
    recorded here because it bears directly on whether a single pathogenic allele
    in a symptomatic adult should be reported.
  evidence:
  - reference: PMID:18408718
    reference_title: "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In all five families, recessive transmission was suggested by the absence
      of the phenotype in the parents of affected sibling pairs; one kindred was
      also notable for parental consanguinity
    explanation: >-
      States the segregation basis for recessive inheritance in the defining
      cohort.
  - reference: PMID:18408718
    reference_title: "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the fourth family, we found a mutation only on the paternal allele;
      however, we did not exclude the presence of other types of mutations, such
      as large deletions, that would not be detectable by sequencing.
    explanation: >-
      Graded PARTIAL because it is the one kindred where biallelic status was
      not demonstrated; it supports the recessive model only under the authors'
      stated assumption about undetected alleles.
  - reference: PMID:23729726
    reference_title: "Iron refractory iron deficiency anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Iron refractory iron deficiency anemia is a hereditary recessive anemia
      due to a defect in the TMPRSS6 gene encoding Matriptase-2.
    explanation: >-
      An independent review restating the recessive inheritance of the entity.
  - reference: PMID:35163840
    reference_title: "Transferrin Saturation/Hepcidin Ratio Discriminates TMPRSS6-Related Iron Refractory Iron Deficiency Anemia from Patients with Multi-Causal Iron Deficiency Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic affected patients typically present in childhood, while
      monoallelic affected patients generally present later in life with a
      milder phenotype regarding the severity of microcytic anemia
    explanation: >-
      Graded PARTIAL because it qualifies the recessive model rather than
      supporting it cleanly: it records a monoallelic patient group with a real,
      milder phenotype, which a strictly recessive model does not predict.
pathophysiology:
- name: Biallelic TMPRSS6 Loss of Function
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >-
    Germline TMPRSS6 variants - frameshift, splice-junction, nonsense and
    missense - on both alleles. In the defining cohort every variant lay distal
    to exon 8, in the region encoding the conserved ectodomain modules and
    especially the trypsin-like serine protease domain, and homozygous
    frameshifts predicted to disrupt only the catalytic domain were sufficient
    to cause disease.

    The reported allelic spectrum has since broadened across the whole large
    ectodomain rather than concentrating in the catalytic domain, which is why a
    novel missense variant outside the protease domain cannot be dismissed on
    position alone.
  genes:
  - preferred_term: TMPRSS6
    term:
      id: hgnc:16517
      label: TMPRSS6
  molecular_functions:
  - preferred_term: matriptase-2 serine protease activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0004252
      label: serine-type endopeptidase activity
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:18408718
    reference_title: "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we show that iron deficiency anemia refractory to oral iron therapy
      can be caused by germline mutations in TMPRSS6, which encodes a type II
      transmembrane serine protease produced by the liver that regulates the
      expression of the systemic iron regulatory hormone hepcidin.
    explanation: >-
      The gene-disease assertion, the protein class, and the hepatic site of
      expression in one sentence.
  - reference: PMID:18408718
    reference_title: "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nonetheless, the finding of individuals with IRIDA harboring homozygous
      frameshift mutations predicted to disrupt only the catalytic domain
      suggests that this portion of the molecule is important for iron
      homeostasis.
    explanation: >-
      Supports catalytic-domain loss as sufficient for the phenotype, which is
      what makes the protease activity the curated molecular function here.
  - reference: PMID:23729726
    reference_title: "Iron refractory iron deficiency anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, 40 different Matriptase-2 mutations have been reported, affecting
      all the functional domains of the large ectodomain of the protein.
    explanation: >-
      Records that the allelic spectrum spans the whole ectodomain rather than
      only the protease domain.
  downstream:
  - target: Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin
    causal_link_type: DIRECT
  - target: Failure to Suppress Hepcidin Transcription in Iron Deficiency
    causal_link_type: DIRECT
- name: Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin
  biological_scale: MOLECULAR
  role: effector
  mechanism_confidence: PROVISIONAL
  description: >-
    Matriptase-2 cleaves haemojuvelin at the plasma membrane. Haemojuvelin is a
    BMP co-receptor that drives HAMP transcription, so removing it from the
    hepatocyte surface lowers hepcidin; failing to remove it keeps hepcidin up.

    Graded PROVISIONAL, and the reason is specific rather than generic caution.
    The supporting evidence is strong for the reaction and weak for the location.
    Eight IRIDA missense alleles were assayed and seven of them impair
    matriptase-2 autoactivation, reduce membrane haemojuvelin cleavage, and fail
    to inhibit haemojuvelin-dependent hepcidin activation - a genotype-activity
    correspondence across human disease alleles, not a single anecdote. But every
    one of those measurements is in transfected cells, none is in a patient
    hepatocyte, and in vivo mouse work finds the liver behaving differently from
    hepatoma cells for an adjacent substrate.

    The sharper problem is that in vivo dissection has since shown the catalytic
    domain to be required for hepcidin suppression while its proteolytic activity
    is not. The cleavage reaction is real and human disease alleles impair it; what
    is in doubt is whether the suppression runs through it. This node is retained
    rather than deleted for that reason, and the discussions carry the argument.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: BMP signaling through membrane hemojuvelin
    modifier: INCREASED
    term:
      id: GO:0030509
      label: BMP signaling pathway
  evidence:
  - reference: PMID:18976966
    reference_title: "The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Matriptase-2 cleaves hemojuvelin (HJV), a regulator of hepcidin, on plasma
      membrane; matriptase-2(MASK) shows no cleavage activity and the human
      mutant only partial cleavage capacity.
    explanation: >-
      Establishes the cleavage reaction and shows it is lost by the mouse mutant
      and reduced by a human disease allele.
  - reference: PMID:23729726
    reference_title: "Iron refractory iron deficiency anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro experiments on transfected cells suggest that Matriptase-2
      cleaves Hemojuvelin, a major regulator of hepcidin expression and that
      this function is altered in this genetic form of anemia.
    explanation: >-
      Graded PARTIAL because the review itself frames the cleavage mechanism as
      what transfected-cell experiments suggest, which is the hedge this node's
      PROVISIONAL grade records.
  - reference: PMID:25156943
    reference_title: "Functional and clinical impact of novel TMPRSS6 variants in iron-refractory iron-deficiency anemia patients and genotype-phenotype studies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All but the p.T287N variant impair matriptase-2 autoproteotylic activation,
      decrease the ability to cleave membrane HJV and inhibit the HJV-dependent
      hepcidin activation.
    explanation: >-
      Extends the cleavage mechanism from one allele to a series of human IRIDA
      missense variants, with an explicit exception.

      The quoted sentence contains the source's own spelling, "autoproteotylic".
      It is a typographical error for "autoproteolytic" and it is reproduced
      exactly because the cache is the authority for a snippet. Do not correct it
      - a tidied quote fails reference validation, which is how this one was
      first noticed.
  downstream:
  - target: Inappropriately Elevated Circulating Hepcidin
    causal_link_type: DIRECT
- name: Failure to Suppress Hepcidin Transcription in Iron Deficiency
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: ESTABLISHED
  description: >-
    The functional lesion stated at the level the disease is actually defined
    by: TMPRSS6 is the component that lets the liver register iron deficiency
    and shut off HAMP transcription. The mask mouse maps this directly - a
    splicing defect in Tmprss6 produces microcytic anaemia through reduced
    dietary iron absorption caused by high hepcidin.

    Note that the mouse work locates the Hamp-suppressing activity in the
    TMPRSS6 cytoplasmic domain acting on proximal promoter elements. That is a
    different molecular route from ectodomain cleavage of haemojuvelin, and the
    two are curated as parallel arms rather than as one chain.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: transcriptional repression of the hepcidin gene HAMP
    modifier: DECREASED
    term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
  evidence:
  - reference: PMID:18451267
    reference_title: "The serine protease TMPRSS6 is required to sense iron deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      TMPRSS6 is an essential component of a pathway that detects iron
      deficiency and blocks Hamp transcription, permitting enhanced dietary iron
      absorption.
    explanation: >-
      The mouse study's summary claim, and the clearest statement of what the
      lost function is.
  - reference: PMID:18451267
    reference_title: "The serine protease TMPRSS6 is required to sense iron deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Overexpression of normal TMPRSS6 protein suppresses activation of the Hamp
      promoter, and the TMPRSS6 cytoplasmic domain mediates Hamp suppression via
      proximal promoter element(s).
    explanation: >-
      Locates the suppressing activity in the cytoplasmic domain - the claim
      that makes this a separate arm from ectodomain haemojuvelin cleavage.
  downstream:
  - target: Inappropriately Elevated Circulating Hepcidin
    causal_link_type: DIRECT
- name: Inappropriately Elevated Circulating Hepcidin
  biological_scale: ORGANISM
  role: effector
  mechanism_confidence: ESTABLISHED
  description: >-
    The pivotal node, and the one that makes the disease diagnosable. Hepcidin
    is normally undetectable in iron deficiency. In IRIDA it is within or above
    the normal range in a patient who is iron deficient - not high in absolute
    terms so much as high for the iron status, which is why a hepcidin value
    read without the transferrin saturation beside it is uninformative.
  biological_processes:
  - preferred_term: systemic iron homeostasis
    term:
      id: GO:0060586
      label: multicellular organismal-level iron ion homeostasis
  evidence:
  - reference: PMID:18408718
    reference_title: "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although urinary hepcidin levels are typically undetectable in individuals
      with iron deficiency
    explanation: >-
      The comparator that makes the IRIDA measurement abnormal; quoted separately
      from the finding itself because it is a statement about ordinary iron
      deficiency, not about IRIDA.
  - reference: PMID:18408718
    reference_title: "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in the five affected individuals from three IRIDA kindreds we examined,
      urinary hepcidin/creatinine ratios were either within or above the normal
      range
    explanation: >-
      The measurement in patients, in five individuals across three kindreds.
  - reference: PMID:23729726
    reference_title: "Iron refractory iron deficiency anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to the low/undetectable hepcidin levels observed in acquired
      iron deficiency, in patients with Matriptase-2 deficiency, serum hepcidin
      is inappropriately high for the low iron status
    explanation: >-
      States the finding as inappropriateness for the iron status rather than
      as an absolute elevation, which is how the node is worded.
  - reference: PMID:42053460
    reference_title: "A Phase 1 Randomized, Double-Blind, Placebo-Controlled Single and Multiple Ascending Dose Study of DISC-3405, a Novel Recombinant Humanized Monoclonal Antibody Targeting TMPRSS6, in Adult Healthy Volunteers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DISC-3405 increased hepcidin-25 and reduced serum iron and transferrin
      saturation across dose levels.
    explanation: >-
      The strongest available causal evidence for this node, and it does not come
      from an IRIDA patient. Pharmacological inhibition of TMPRSS6 in healthy
      volunteers raised hepcidin and lowered serum iron and transferrin
      saturation - the human biochemistry of IRIDA, produced deliberately, in a
      randomised placebo-controlled design.
  downstream:
  - target: Impaired Duodenal Iron Absorption
    causal_link_type: DIRECT
  - target: Macrophage Iron Sequestration
    causal_link_type: DIRECT
- name: Impaired Duodenal Iron Absorption
  biological_scale: TISSUE
  role: effector
  mechanism_confidence: ESTABLISHED
  description: >-
    Hepcidin restricts iron entry into plasma at the basolateral surface of the
    duodenal enterocyte. With hepcidin high, dietary iron - whether from food or
    from an oral supplement - is not delivered to the circulation, which is the
    direct explanation for refractoriness to oral iron.
  locations:
  - preferred_term: duodenum
    term:
      id: UBERON:0002114
      label: duodenum
  cell_types:
  - preferred_term: duodenal enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  biological_processes:
  - preferred_term: intestinal iron absorption
    modifier: DECREASED
    term:
      id: GO:0050892
      label: intestinal absorption
  - preferred_term: iron export across the basolateral enterocyte membrane
    modifier: DECREASED
    term:
      id: GO:0034755
      label: iron ion transmembrane transport
  evidence:
  - reference: PMID:18451267
    reference_title: "The serine protease TMPRSS6 is required to sense iron deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Hepcidin, a liver-derived protein that restricts enteric iron absorption,
      is the key regulator of body iron content.
    explanation: >-
      The general mechanism by which raised hepcidin blocks absorption.
  - reference: PMID:18451267
    reference_title: "The serine protease TMPRSS6 is required to sense iron deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The mask phenotype results from reduced absorption of dietary iron caused
      by high levels of hepcidin and is due to a splicing defect in the
      transmembrane serine protease 6 gene Tmprss6.
    explanation: >-
      Demonstrates the hepcidin-to-malabsorption step in the Tmprss6-deficient
      animal.
  - reference: PMID:18408718
    reference_title: "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      it may explain the failure to absorb dietary iron despite systemic iron
      deficiency
    explanation: >-
      The authors' own reading of what raised hepcidin explains in their
      patients.
  - reference: PMID:35163840
    reference_title: "Transferrin Saturation/Hepcidin Ratio Discriminates TMPRSS6-Related Iron Refractory Iron Deficiency Anemia from Patients with Multi-Causal Iron Deficiency Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Since hepcidin impairs intestinal iron absorption and recycling by
      inhibiting ferroportin-mediated iron export from enterocytes and
      macrophages
    explanation: >-
      Names ferroportin as the effector hepcidin acts on, which is the molecular
      step this node and the macrophage node share.
  downstream:
  - target: Systemic Iron Restriction
    causal_link_type: DIRECT
- name: Macrophage Iron Sequestration
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: ESTABLISHED
  description: >-
    The second, less obvious limb, and the one that explains why parenteral iron
    is not a clean rescue. Hepcidin also blocks iron release from macrophages.
    Parenteral iron formulations are taken up by the reticuloendothelial system
    and must be re-exported before erythroid precursors can use them, so a
    hepcidin block downstream of the injection limits the response even when the
    gut has been bypassed entirely.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: macrophage iron release into plasma
    modifier: DECREASED
    term:
      id: GO:0034755
      label: iron ion transmembrane transport
  evidence:
  - reference: PMID:18408718
    reference_title: "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hepcidin, a hormone produced by the liver that regulates intestinal iron
      absorption and macrophage iron release
    explanation: >-
      Establishes macrophage iron release as the second hepcidin-regulated step.
  - reference: PMID:18408718
    reference_title: "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      as well as the coexistent failure to respond to parenteral iron
      administered as iron-dextran, which must be processed and exported by
      macrophages before utilization for erythropoiesis
    explanation: >-
      Ties the macrophage block specifically to the incomplete parenteral-iron
      response, which is the clinically visible consequence of this node.
  - reference: PMID:35163840
    reference_title: "Transferrin Saturation/Hepcidin Ratio Discriminates TMPRSS6-Related Iron Refractory Iron Deficiency Anemia from Patients with Multi-Causal Iron Deficiency Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Since hepcidin impairs intestinal iron absorption and recycling by
      inhibiting ferroportin-mediated iron export from enterocytes and
      macrophages
    explanation: >-
      The macrophage half of the same ferroportin statement, which is what makes
      recycling as well as absorption hepcidin-dependent.
  - reference: PMID:35163840
    reference_title: "Transferrin Saturation/Hepcidin Ratio Discriminates TMPRSS6-Related Iron Refractory Iron Deficiency Anemia from Patients with Multi-Causal Iron Deficiency Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in IRIDA patients ferritin levels are generally within the low-normal range
      before the start of IV iron treatment due to iron maldistribution, in which
      inappropriately high hepcidin levels lead to iron sequestration in
      macrophages
    explanation: >-
      The human-measurable readout of this node. Iron is not absent from the body
      but misplaced, and the ferritin level is where that shows: low-normal rather
      than the low value acquired iron deficiency would give.
  downstream:
  - target: Systemic Iron Restriction
    causal_link_type: DIRECT
- name: Systemic Iron Restriction
  biological_scale: ORGANISM
  role: effector
  mechanism_confidence: ESTABLISHED
  description: >-
    Both limbs converge on a reduced supply of transferrin-bound iron to the
    marrow. The biochemical shadow of this node is the low transferrin
    saturation that, together with a non-suppressed hepcidin, defines the
    diagnostic pattern.
  biological_processes:
  - preferred_term: systemic iron homeostasis
    modifier: DECREASED
    term:
      id: GO:0060586
      label: multicellular organismal-level iron ion homeostasis
  evidence:
  - reference: PMID:23729726
    reference_title: "Iron refractory iron deficiency anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hallmarks of this disease are microcytic hypochromic anemia, low
      transferrin saturation and normal/high serum hepcidin values.
    explanation: >-
      The three-part laboratory signature, of which low transferrin saturation
      is this node's readout.
  downstream:
  - target: Iron-Restricted Erythropoiesis
    causal_link_type: DIRECT
- name: Iron-Restricted Erythropoiesis
  biological_scale: TISSUE
  role: consequence
  mechanism_confidence: ESTABLISHED
  description: >-
    Erythroid precursors deprived of iron undergo extra divisions and produce
    small, poorly haemoglobinised red cells. The marrow itself is not the
    diseased compartment - it is a normal marrow starved of substrate - which is
    why the anaemia is typically moderate and non-progressive rather than
    transfusion-dependent.
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  cell_types:
  - preferred_term: erythroid progenitor cell
    term:
      id: CL:0000038
      label: erythroid progenitor cell
  evidence:
  - reference: PMID:23729726
    reference_title: "Iron refractory iron deficiency anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hallmarks of this disease are microcytic hypochromic anemia, low
      transferrin saturation and normal/high serum hepcidin values.
    explanation: >-
      The erythroid output of the restricted supply - microcytic, hypochromic
      red cells.
  - reference: PMID:18451267
    reference_title: "The serine protease TMPRSS6 is required to sense iron deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We describe mask: a recessive, chemically induced mutant mouse phenotype,
      characterized by progressive loss of body (but not facial) hair and
      microcytic anemia.
    explanation: >-
      The same erythroid consequence in the Tmprss6-deficient mouse. Graded
      MODEL_ORGANISM and kept distinct from the human evidence above.
phenotypes:
- category: Hematological
  name: Hypochromic Microcytic Anemia
  frequency: OBLIGATE
  description: >-
    The presenting and defining abnormality. It appears in the post-natal period
    but is mild enough in some patients that it is first recognised in
    adulthood, which is a common route to long-delayed diagnosis.
  phenotype_term:
    preferred_term: Hypochromic microcytic anemia
    term:
      id: HP:0004840
      label: Hypochromic microcytic anemia
  notes: >-
    Kept at OBLIGATE for the anaemia, which no report contradicts, but the
    *microcytosis* is not universal: a proband in one of six Saudi IRIDA families
    presented with normocytic anaemia and a normal MCV. That is curated on the
    separate MCV phenotype below, which is banded VERY_FREQUENT rather than
    OBLIGATE for exactly this reason. Splitting the anaemia from its red-cell
    indices is what lets the entry hold both facts.
  evidence:
  - reference: PMID:23729726
    reference_title: "Iron refractory iron deficiency anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hallmarks of this disease are microcytic hypochromic anemia, low
      transferrin saturation and normal/high serum hepcidin values.
    explanation: >-
      Names the anaemia as a hallmark of the disease.
  - reference: PMID:23729726
    reference_title: "Iron refractory iron deficiency anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The anemia appears in the post-natal period, although in some cases it is
      only diagnosed in adulthood.
    explanation: >-
      Supports the onset statement and the diagnostic-delay note in the
      description.
- category: Laboratory
  name: Very Low Mean Corpuscular Volume
  frequency: VERY_FREQUENT
  description: >-
    Microcytosis in IRIDA is characteristically severe, which is part of why the
    disease is mistaken for thalassaemia trait.
  phenotype_term:
    preferred_term: Decreased mean corpuscular volume
    term:
      id: HP:0025066
      label: Decreased mean corpuscular volume
  evidence:
  - reference: PMID:18408718
    reference_title: "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a congenital hypochromic, microcytic anemia, a very low mean corpuscular
      erythrocyte volume, a low transferrin saturation
    explanation: >-
      Lists a very low MCV among the key features defining the phenotype.
  - reference: PMID:36261087
    reference_title: "TMPRSS6 gene mutations in six Saudi families with iron refractory iron deficiency anemia."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband of family 6 presented numerous hematological abnormalities upon
      initial consultation, including normocytic anemia accompanied by low Hb,
      normal MCV, low serum iron, low serum ferritin, and normal TIBC.
    explanation: >-
      Graded REFUTE against microcytosis being universal. One proband of six
      families had a normal MCV, which is why this phenotype is VERY_FREQUENT
      rather than OBLIGATE. Note this patient also had *low* ferritin, so the
      ferritin phenotype above is likewise not universal.
- category: Laboratory
  name: Low Transferrin Saturation
  frequency: VERY_FREQUENT
  description: >-
    Reflects the restricted supply of iron to plasma. It is the value that must
    be read alongside hepcidin for the hepcidin result to be interpretable.
  phenotype_term:
    preferred_term: Decreased transferrin saturation
    term:
      id: HP:0012464
      label: Decreased transferrin saturation
  evidence:
  - reference: PMID:23729726
    reference_title: "Iron refractory iron deficiency anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hallmarks of this disease are microcytic hypochromic anemia, low
      transferrin saturation and normal/high serum hepcidin values.
    explanation: >-
      Names low transferrin saturation as a hallmark.
  - reference: PMID:18408718
    reference_title: "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In all cases, Hb, MCV and transferrin saturation were below the respective
      reference ranges provided by the referring hospital laboratory.
    explanation: >-
      Confirms the finding held across every index case in the defining cohort.
- category: Laboratory
  name: Hepcidin Not Suppressed Despite Iron Deficiency
  frequency: VERY_FREQUENT
  description: >-
    The discriminating laboratory finding, and the reason a single hepcidin
    assay can separate IRIDA from acquired iron deficiency. The abnormality is
    relative, not absolute: values sit within or above the normal range at a time
    when they should be undetectable.

    Curated as VERY_FREQUENT rather than OBLIGATE deliberately. It is
    mechanistically obligate, but the published human measurements are five
    individuals from three kindreds in the defining paper plus subsequent series,
    and hepcidin assays were not standardised across them - so the frequency
    band records what has been measured rather than what the model predicts.
  phenotype_term:
    preferred_term: Elevated circulating hepcidin concentration
    term:
      id: HP:0031877
      label: Elevated circulating hepcidin concentration
  evidence:
  - reference: PMID:18408718
    reference_title: "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The finding of inappropriately elevated urinary hepcidin levels in
      individuals with IRIDA provides insight into the pathophysiology of the
      disorder
    explanation: >-
      The primary measurement of non-suppressed hepcidin in patients.
  - reference: PMID:23729726
    reference_title: "Iron refractory iron deficiency anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to the low/undetectable hepcidin levels observed in acquired
      iron deficiency, in patients with Matriptase-2 deficiency, serum hepcidin
      is inappropriately high for the low iron status
    explanation: >-
      States the contrast with acquired iron deficiency that gives the finding
      its discriminating value.
- category: Laboratory
  name: Serum Ferritin Inappropriately Preserved
  frequency: VERY_FREQUENT
  description: >-
    The lab value that most cleanly separates IRIDA from acquired iron deficiency,
    and it separates them by not being low enough. Ferritin in IRIDA sits in the
    low-normal range because the body's iron is misplaced rather than absent -
    hepcidin holds it in macrophages - whereas in acquired deficiency the stores
    really are empty. Measured head to head, ferritin was significantly higher in
    IRIDA patients than in iron-deficient controls at p < 0.001.

    The direction of the abnormality is therefore the opposite of what "iron
    deficiency anaemia" leads a reader to expect, which is why it is curated as a
    phenotype in its own right rather than left implicit.
  phenotype_term:
    preferred_term: Serum ferritin inappropriately preserved for the degree of iron deficiency
    term:
      id: HP:0040133
      label: Abnormal circulating ferritin concentration
  evidence:
  - reference: PMID:35163840
    reference_title: "Transferrin Saturation/Hepcidin Ratio Discriminates TMPRSS6-Related Iron Refractory Iron Deficiency Anemia from Patients with Multi-Causal Iron Deficiency Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the IRIDA group, MCV levels were significantly lower and ferritin levels
      significantly higher in comparison with the IDA group (p = 0.01 and p <
      0.001).
    explanation: >-
      The head-to-head comparison against iron-deficient controls, with both
      directions and both p values.
  - reference: PMID:35163840
    reference_title: "Transferrin Saturation/Hepcidin Ratio Discriminates TMPRSS6-Related Iron Refractory Iron Deficiency Anemia from Patients with Multi-Causal Iron Deficiency Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      develop microcytic anemia with remarkably low transferrin saturation (TSAT),
      low-normal ferritin levels, and a poor response to oral iron treatment
    explanation: >-
      States the expected ferritin range in IRIDA alongside the other two elements
      of the laboratory signature.
  notes: >-
    Bound to the general term HP:0040133 "Abnormal circulating ferritin
    concentration" rather than to the increased or decreased child terms, and the
    choice is deliberate. The finding is neither: it is a value that would be
    unremarkable in isolation and is abnormal only relative to the iron status.
    This is the same ontology gap as the hepcidin binding in this entry - HPO
    represents direction of change but not inappropriateness for a physiological
    context - and both are recorded in `notes` rather than papered over with a
    child term that asserts a direction the patients do not reliably show.
- category: Laboratory
  name: Hyperferritinemia at Presentation
  frequency: VERY_RARE
  description: >-
    A documented departure from the expected picture: two French-Canadian siblings
    presented with severe microcytic anaemia, hypoferremia and *raised* ferritin,
    a combination that fits no previously described genetic iron-deficiency
    anaemia, and both were carrying compound heterozygous TMPRSS6 variants
    previously reported to cause classic IRIDA.

    Curated because it is the presentation that would stop a clinician
    considering the diagnosis, and because the same kindred is the counterexample
    to oral-iron refractoriness recorded below.
  phenotype_term:
    preferred_term: Increased circulating ferritin concentration
    term:
      id: HP:0003281
      label: Increased circulating ferritin concentration
  evidence:
  - reference: PMID:23319530
    reference_title: "Iron refractory iron deficiency anemia: presentation with hyperferritinemia and response to oral iron therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a French-Canadian kindred in which 2 siblings presented in early
      childhood with severe microcytic anemia, hypoferremia, and
      hyperferritinemia. Both children have been successfully treated solely with
      low-dose oral iron since diagnosis.
    explanation: >-
      The presentation and, in the same sentence, the treatment response that
      makes this kindred doubly exceptional.
  - reference: PMID:23319530
    reference_title: "Iron refractory iron deficiency anemia: presentation with hyperferritinemia and response to oral iron therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing identified in both patients compound heterozygous
      mutations of TMPRSS6 leading to p.G442R and p.E522K, 2 mutations previously
      reported to cause classic IRIDA
    explanation: >-
      Establishes that the atypical presentation is not explained by atypical
      alleles - both variants had already been reported in classic IRIDA.
- category: Treatment Response
  name: Refractoriness to Oral Iron
  frequency: VERY_FREQUENT
  description: >-
    Not a symptom but a therapeutic-response phenotype, and it is close to being
    part of the disease definition rather than an outcome of it - the entity was
    delimited by the failure of oral iron in multiplex kindreds before the gene
    was known. Curated here so it is queryable rather than buried in the treatment
    section.

    Banded VERY_FREQUENT rather than OBLIGATE, and the demotion is evidence-led
    rather than cautious. Two siblings with compound heterozygous TMPRSS6 variants
    already reported in classic IRIDA have been maintained on low-dose oral iron
    alone since diagnosis. One published exception is enough to make an OBLIGATE
    band false, and this exception is well characterised: genotype-confirmed, and
    reported precisely because it expands the disease spectrum.
  phenotype_term:
    preferred_term: Iron deficiency anemia unresponsive to oral iron
    term:
      id: HP:0001891
      label: Iron deficiency anemia
  evidence:
  - reference: PMID:18408718
    reference_title: "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      abnormal iron absorption characterized by no hematological improvement
      following treatment with oral iron
    explanation: >-
      Oral-iron refractoriness as one of the defining key features of the
      phenotype.
  - reference: PMID:25064705
    reference_title: "Iron-refractory iron deficiency anemia (IRIDA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      multiple family members are affected with iron deficiency anemia that is
      unresponsive to oral iron supplementation and only partially responsive to
      parenteral iron therapy
    explanation: >-
      Independent restatement, and it also records the partial parenteral
      response curated as its own phenotype below.
  - reference: PMID:23319530
    reference_title: "Iron refractory iron deficiency anemia: presentation with hyperferritinemia and response to oral iron therapy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, the phenotype associated with the unique combination of mutations
      uncovered in both patients expands the spectrum of disease associated with
      TMPRSS6 mutations to include iron deficiency anemia that is accompanied by
      hyperferritinemia at initial presentation and is responsive to continued
      oral iron therapy.
    explanation: >-
      Graded REFUTE against the claim that oral-iron refractoriness is obligate.
      This is the counterexample that sets the frequency band, and it is quoted
      from the authors' own conclusion rather than inferred from their case
      description.
  notes: >-
    The HP binding is deliberately the general term HP:0001891 "Iron deficiency
    anemia". HPO has no term for refractoriness to a specific therapy, so the
    treatment-response part of this phenotype lives in preferred_term and the
    description rather than in the ontology binding. Do not substitute a
    narrower-sounding term that does not mean this.

    Note the tension this phenotype now carries and should keep carrying: the
    disease is *named* for oral-iron refractoriness, and a genotype-confirmed
    kindred responds to oral iron. Both are true. Resolving it by dropping either
    the name or the exception would lose information.
- category: Treatment Response
  name: Incomplete Response to Parenteral Iron
  frequency: VERY_FREQUENT
  description: >-
    Distinguishes IRIDA from a pure absorption defect. Bypassing the gut helps,
    but only slowly and partially, because the injected iron still has to leave
    the macrophage compartment against a hepcidin block.
  phenotype_term:
    preferred_term: Iron deficiency anemia only partially corrected by parenteral iron
    term:
      id: HP:0001891
      label: Iron deficiency anemia
  evidence:
  - reference: PMID:23729726
    reference_title: "Iron refractory iron deficiency anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease is refractory to oral iron treatment but shows a slow response
      to intravenous iron injections and partial correction of the anemia.
    explanation: >-
      States both the partial nature and the slowness of the parenteral
      response.
  - reference: PMID:18408718
    reference_title: "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      abnormal iron utilization characterized by a sluggish, incomplete response
      to parenteral iron
    explanation: >-
      The same finding in the defining cohort, described as a utilisation rather
      than an absorption defect.
biochemical:
- name: Serum hepcidin
  presence: PRESENT
  biomarker_term:
    preferred_term: Elevated circulating hepcidin concentration
    term:
      id: HP:0031877
      label: Elevated circulating hepcidin concentration
  evidence:
  - reference: PMID:23729726
    reference_title: "Iron refractory iron deficiency anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hallmarks of this disease are microcytic hypochromic anemia, low
      transferrin saturation and normal/high serum hepcidin values.
    explanation: >-
      Establishes serum hepcidin as a hallmark laboratory measurement in the
      disease.
  notes: >-
    The single most informative test in the differential, precisely because the
    abnormality is directional rather than a threshold crossing. A hepcidin value
    that would be unremarkable in a healthy person is abnormal in a patient with
    a transferrin saturation of five percent.

    No reference range is curated here on purpose. Hepcidin immunoassays and
    mass-spectrometry methods are not harmonised, absolute values are not
    comparable between laboratories, and there is no consensus adult interval to
    cite - so a numeric range in this entry would be a false precision. See the
    knowledge-gap discussion on assay standardisation.
- name: Transferrin saturation
  presence: PRESENT
  biomarker_term:
    preferred_term: Decreased transferrin saturation
    term:
      id: HP:0012464
      label: Decreased transferrin saturation
  evidence:
  - reference: PMID:18408718
    reference_title: "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transferrin saturation (%) was calculated by dividing the serum iron level
      by the total iron binding capacity and multiplying by 100.
    explanation: >-
      The measurement definition used to characterise the defining cohort.
  notes: >-
    Low, and required to interpret the hepcidin result. The pair is the test, not
    either value alone.
definitions:
- name: Transferrin saturation to hepcidin ratio
  definition_type: PHENOTYPE_ALGORITHM
  derivation_basis: ESTABLISHED_CRITERIA
  scope: >-
    Early discrimination of TMPRSS6-related IRIDA from other causes of iron
    deficiency anaemia, in a patient already found to be iron deficient.
  description: >-
    A single computable quantity - transferrin saturation in percent divided by
    plasma hepcidin-25 in nM - with a derived threshold of 5.6 %/nM. Below the
    threshold suggests IRIDA; above it suggests iron deficiency from another
    cause.

    The ratio is the right form for this test because the abnormality it detects
    is relative. Neither the transferrin saturation nor the hepcidin level is
    diagnostic alone: a patient with acquired iron deficiency and an IRIDA patient
    can share a transferrin saturation, and a hepcidin value that is normal in
    absolute terms is the abnormal finding here. Dividing one by the other is what
    turns "inappropriately high for the iron status" into a number.

    Two preconditions are part of the rule, not caveats attached to it. It applies
    only when the patient has had no iron therapy in the preceding three months and
    has no moderate-to-severe inflammation, because both raise hepcidin
    independently of TMPRSS6 and would push a control across the threshold.
  inclusion_criteria:
  - preferred_term: Established iron deficiency anaemia
    description: Iron deficiency anaemia already demonstrated on standard haematological and iron indices.
  - preferred_term: No iron therapy in the previous three months
    description: >-
      The derivation cohort's controls were required to be iron-therapy naive over
      this window, because administered iron raises hepcidin directly.
  - preferred_term: C-reactive protein below 10.0 mg/L
    description: >-
      The inflammation ceiling used in the derivation study, excluding
      moderate-to-severe inflammation.
  - preferred_term: Hepcidin-25 measured by a mass-spectrometry-calibrated method
    description: >-
      The threshold is expressed in nM against standardised isotope dilution mass
      spectrometry and is not portable to an uncalibrated immunoassay.
  exclusion_criteria:
  - preferred_term: Recent oral or parenteral iron therapy
    description: >-
      Raises hepcidin independently of TMPRSS6 and can move an IRIDA patient above
      the threshold, producing a false negative.
  - preferred_term: Moderate-to-severe inflammation
    description: >-
      Raises hepcidin through the inflammatory axis and reproduces the IRIDA
      pattern in a patient who does not have it.
  validation_status:
    status: VALIDATED_AGAINST_GOLD_STANDARD
    rationale: >-
      Validated against TMPRSS6 genotype as the reference standard, which is the
      correct gold standard for this question, and the discrimination was
      complete: area under the curve 1.000, sensitivity and specificity both 100%.

      Recorded as VALIDATED_AGAINST_GOLD_STANDARD on that basis, with the
      qualification that this is a derivation study rather than an external
      validation. Twenty registry-ascertained IRIDA patients and 39 selected
      controls is a small and enriched sample; the confidence intervals the
      authors report are the honest summary of the precision, and they themselves
      ask for further exploration in a broader population. No independent cohort
      has been reported applying the 5.6 %/nM threshold.
    evidence:
    - reference: PMID:35163840
      reference_title: "Transferrin Saturation/Hepcidin Ratio Discriminates TMPRSS6-Related Iron Refractory Iron Deficiency Anemia from Patients with Multi-Causal Iron Deficiency Anemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The area under the curve for the TSAT/hepcidin ratio was 1.000 with 100%
        sensitivity and specificity (95% confidence intervals 84-100% and
        91-100%, respectively) at an optimal cut-off point of 5.6%/nM.
      explanation: >-
        The operating characteristics and the threshold, together with the
        confidence intervals that carry the precision.
  evidence:
  - reference: PMID:35163840
    reference_title: "Transferrin Saturation/Hepcidin Ratio Discriminates TMPRSS6-Related Iron Refractory Iron Deficiency Anemia from Patients with Multi-Causal Iron Deficiency Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IRIDA patients had significantly lower TSAT/hepcidin ratios compared to IDA
      controls, median 0.6%/nM (interquartile range, IQR, 0.4-1.1%/nM) and
      16.7%/nM (IQR, 12.0-24.0%/nM), respectively.
    explanation: >-
      The separation the threshold sits inside, with both group distributions
      given rather than only the cut-off.
  - reference: PMID:35163840
    reference_title: "Transferrin Saturation/Hepcidin Ratio Discriminates TMPRSS6-Related Iron Refractory Iron Deficiency Anemia from Patients with Multi-Causal Iron Deficiency Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The TSAT/hepcidin ratio shows excellent performance in discriminating IRIDA
      from TMPRSS6-unrelated IDA early in the diagnostic work-up of IDA provided
      that recent iron therapy and moderate-to-severe inflammation are absent.
    explanation: >-
      Graded PARTIAL because the sentence carries its own conditions: the
      performance claim holds only under the two exclusions curated above, which
      is why they are inclusion criteria of the rule rather than footnotes to it.
  attaches_to:
  - "biochemical#Serum hepcidin"
  - "biochemical#Transferrin saturation"
  - "pathophysiology#Inappropriately Elevated Circulating Hepcidin"
  notes: >-
    The 5.6 %/nM threshold is method-bound. Hepcidin was measured by standardised
    isotope dilution mass spectrometry, and routine hepcidin immunoassays are not
    calibrated to it, so the numeric cut-off cannot be carried to another
    laboratory without cross-calibration. Applying it to an uncalibrated
    immunoassay result would be a units error dressed as a diagnosis.
genetic:
- name: TMPRSS6
  gene_term:
    preferred_term: TMPRSS6
    term:
      id: hgnc:16517
      label: TMPRSS6
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  features: >-
    TMPRSS6 encodes matriptase-2, a type II transmembrane serine protease
    expressed primarily in the liver. Its ectodomain carries CUB and LDL-receptor
    class A modules and a trypsin-like serine protease domain; the mutations
    reported in IRIDA span all of these.
  notes: >-
    Two points that matter when interpreting a new variant.

    First, the disease-associated allelic spectrum is broad. The defining cohort
    found frameshift, splice-junction, nonsense and missense variants, all distal
    to exon 8, and by 2013 forty distinct alleles had been reported across the
    whole large ectodomain. Absence from the catalytic domain is not reassuring.

    Second, and less widely appreciated, common TMPRSS6 variation is a
    quantitative modifier of iron status in the general population as well as a
    cause of this Mendelian disease. This entry curates only the biallelic
    loss-of-function disease; the common-variant association is a different claim
    with a different evidence base and is deliberately not asserted here.

    Third, genotype carries prognostic information. Patients with two nonsense
    alleles have more severe anaemia and microcytosis and higher hepcidin than
    other genotypes, which is the expected direction if residual matriptase-2
    activity is what sets hepcidin. That correlation is drawn from a series of 21
    patients and should be read as a tendency, not a rule for an individual.
  evidence:
  - reference: PMID:18408718
    reference_title: "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals harbored frame-shift mutations, splice junction
      mutations or missense mutations altering residues conserved
    explanation: >-
      The classes of variant found, supporting the loss-of-function mechanism.
  - reference: PMID:18408718
    reference_title: "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      None of the disease-associated variants were present in the NCBI and
      Ensembl SNP databases or in 100 control chromosomes
    explanation: >-
      Population-absence evidence for pathogenicity of the reported alleles.
  - reference: PMID:25064705
    reference_title: "Iron-refractory iron deficiency anemia (IRIDA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The discovery that many of these cases harbor mutations in the TMPRSS6
      gene led to the recognition that they represent a single clinical entity:
      iron-refractory iron deficiency anemia (IRIDA).
    explanation: >-
      Independent statement that TMPRSS6 genotype is what delimits the entity.
  - reference: PMID:25156943
    reference_title: "Functional and clinical impact of novel TMPRSS6 variants in iron-refractory iron-deficiency anemia patients and genotype-phenotype studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our genotype-phenotype correlation analysis demonstrates that patients
      carrying two nonsense mutations present a more severe anemia and
      microcytosis and higher hepcidin levels than the other patients.
    explanation: >-
      The genotype-severity correlation recorded in the notes above.
  - reference: PMID:25156943
    reference_title: "Functional and clinical impact of novel TMPRSS6 variants in iron-refractory iron-deficiency anemia patients and genotype-phenotype studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We confirm that TMPRSS6 mutations are spread along the gene and that
      mechanistically they fully or partially abrogate hepcidin inhibition.
    explanation: >-
      Supports the statement that the allelic spectrum is not confined to the
      catalytic domain, and that the functional effect is graded rather than
      binary.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population prevalence estimate is published. The literature describes the
    entity through kindreds and case series rather than through an epidemiological
    denominator, and the closest quantitative anchor is the count of distinct
    reported TMPRSS6 alleles - forty by 2013 - which counts mutations, not
    patients, and is recorded here only as an order-of-magnitude indication that
    the reported population is small.

    rate_per_100000 is deliberately left empty. Deriving a rate from an allele
    count would be an invention.
  evidence:
  - reference: PMID:23729726
    reference_title: "Iron refractory iron deficiency anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, 40 different Matriptase-2 mutations have been reported, affecting
      all the functional domains of the large ectodomain of the protein.
    explanation: >-
      Graded PARTIAL: it bounds the size of the reported literature but is a
      count of alleles rather than of patients, and is not a prevalence
      measurement.
treatments:
- name: Parenteral Iron
  description: >-
    The mainstay of treatment. It bypasses the blocked duodenal step but not the
    macrophage one, so the response is slow and the correction partial rather
    than complete.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: iron
      term:
        id: CHEBI:29033
        label: iron(2+)
  target_mechanisms:
  - target: Impaired Duodenal Iron Absorption
    treatment_effect: BYPASSES
    description: >-
      Delivering iron intravenously circumvents the enterocyte export block
      entirely. It does nothing about the hepcidin elevation that caused it,
      which is why this is curated as BYPASSES rather than INHIBITS or RESTORES.
    evidence:
    - reference: PMID:23729726
      reference_title: "Iron refractory iron deficiency anemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The disease is refractory to oral iron treatment but shows a slow
        response to intravenous iron injections and partial correction of the
        anemia.
      explanation: >-
        Supports parenteral iron as effective where oral iron is not, and records
        that the correction is partial.
  evidence:
  - reference: PMID:23729726
    reference_title: "Iron refractory iron deficiency anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The current treatment of iron refractory iron deficiency anemia is based
      on parenteral iron administration
    explanation: >-
      Names parenteral iron as the current standard of care.
- name: Oral Iron
  description: >-
    Curated because it is what patients are given for years before the diagnosis
    is made, not because it works. It does not.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: iron
      term:
        id: CHEBI:29033
        label: iron(2+)
  evidence:
  - reference: PMID:18408718
    reference_title: "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      abnormal iron absorption characterized by no hematological improvement
      following treatment with oral iron
    explanation: >-
      Graded REFUTE against the claim that oral iron treats this disease. The
      quoted finding is a negative therapeutic result and is the reason the
      entity has "refractory" in its name.
  - reference: PMID:30594846
    reference_title: "Favourable improvement in haematological parameters in response to oral iron and vitamin C combination in children with Iron Refractory Iron Deficiency Anemia (IRIDA) phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We prospectively evaluated our IRIDA cohort (n = 7) with oral iron and
      vitamin c dose over a period of 10 weeks and noted complete response in
      majority (6/7 = 86%) with >2 g/dL rise in Hb along with significant
      improvement of other iron related indices.
    explanation: >-
      Points the other way from the item above and is graded PARTIAL rather than
      SUPPORT for two reasons stated by the source itself. The cohort is seven
      children, uncontrolled and unblinded; and the paper's own title describes
      them as having the IRIDA *phenotype*, not confirmed biallelic TMPRSS6
      genotype, so some may have had oral-iron-responsive iron deficiency that
      IRIDA was never the explanation for. This is evidence that the combination
      deserves a trial, not that the refractoriness claim is wrong.
  notes: >-
    No target_mechanisms link is curated for oral iron, and the omission is
    deliberate: the drug does not act on any node in this pathograph, which is
    precisely the clinical point. That holds for the ascorbate combination too -
    ascorbate acts on luminal iron reduction and uptake, upstream of the
    ferroportin export step that hepcidin blocks, so even a real effect would not
    be acting on a node curated here.

    The two evidence items on this treatment deliberately disagree, and the
    disagreement is the content. One is a defining-cohort negative result, the
    other a seven-patient uncontrolled positive result in a phenotypically
    defined group. Collapsing them to a single grade would misrepresent the
    literature.
- name: Hepcidin-Lowering Therapy
  description: >-
    Not an available treatment. Curated as a stated therapeutic direction because
    the mechanism identifies the target unusually cleanly - the disease is caused
    by hepcidin that is too high, so an agent that lowers it would address the
    lesion rather than its consequence.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:23729726
    reference_title: "Iron refractory iron deficiency anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in the future, manipulation of the hepcidin pathway with the aim of
      suppressing it might become an alternative therapeutic approach
    explanation: >-
      Graded PARTIAL because the source states this as a prospect, not as a
      demonstrated therapy. No clinical trial in IRIDA is cited here, and none
      should be inferred from this item.
  notes: >-
    Deliberately carries no target_mechanisms link and no therapeutic_agent.
    Linking a hypothetical agent to the hepcidin node would render an arrow on
    the pathograph asserting a therapeutic action that has not been demonstrated
    in this disease.
animal_models:
- name: mask mouse (Tmprss6 splice-site mutant)
  species: Mouse
  genotype: Tmprss6 mask, homozygous ENU-induced splicing defect
  publication: PMID:18451267
  description: >-
    A chemically induced recessive mouse mutant recovered on phenotype - hair
    loss and microcytic anaemia - and mapped to a Tmprss6 splicing defect. It is
    the model that established what the human gene does, and it was published
    within weeks of the human gene discovery.
  modeled_mechanisms:
  - target: Failure to Suppress Hepcidin Transcription in Iron Deficiency
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The mouse reproduces the core lesion - Tmprss6 loss, high hepcidin, reduced
      dietary iron absorption, microcytic anaemia - and is the system in which the
      Hamp-promoter mechanism was demonstrated.
    limitations: >-
      One phenotypic divergence is worth stating rather than glossing. The mouse
      is named for progressive loss of body but not facial hair, and alopecia of
      this kind is not a feature of human IRIDA. Whatever produces the mask coat
      phenotype is therefore either mouse-specific or an aspect of matriptase-2
      biology that human patients do not show, and it should not be used to
      predict a human phenotype.
    readouts:
    - name: Red cell volume and dietary iron absorption
      target: Failure to Suppress Hepcidin Transcription in Iron Deficiency
      direction: DECREASED
      interpretation: >-
        Microcytic anaemia resulting from reduced dietary iron absorption, the
        mouse counterpart of the human erythroid phenotype.
      evidence:
      - reference: PMID:18451267
        reference_title: "The serine protease TMPRSS6 is required to sense iron deficiency."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          The mask phenotype results from reduced absorption of dietary iron
          caused by high levels of hepcidin and is due to a splicing defect in
          the transmembrane serine protease 6 gene Tmprss6.
        explanation: >-
          Reports the measured absorption defect and its hepcidin cause in the
          mutant.
    evidence:
    - reference: PMID:18451267
      reference_title: "The serine protease TMPRSS6 is required to sense iron deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        TMPRSS6 is an essential component of a pathway that detects iron
        deficiency and blocks Hamp transcription, permitting enhanced dietary
        iron absorption.
      explanation: >-
        Supports treating this model as informative for the hepcidin-suppression
        node.
experimental_models:
- name: Matriptase-2 hemojuvelin cleavage assay in transfected cells
  experimental_model_type: CELL_LINE
  description: >-
    Co-expression of matriptase-2 - wild type, the mask truncation, or the human
    disease allele R774C - with haemojuvelin in cultured cells, read out by
    hepcidin promoter activity and by cleavage of membrane haemojuvelin.
  modeled_mechanisms:
  - target: Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Demonstrates the proposed enzymatic step and shows it is graded by
      genotype: absent for the mouse truncation, partial for the human missense
      allele.
    limitations: >-
      Overexpression in a heterologous cell line rather than a hepatocyte
      carrying the variant at its endogenous locus, so the assay establishes that
      the reaction can occur and is genotype-sensitive, not that it is the
      rate-limiting step in a patient's liver. Fidelity is graded MODERATE on
      that basis.
    readouts:
    - name: Membrane hemojuvelin cleavage by matriptase-2 variants
      target: Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin
      direction: DECREASED
      interpretation: >-
        Cleavage is abolished by the mask truncation and reduced by the human
        R774C allele relative to wild-type matriptase-2.
      evidence:
      - reference: PMID:18976966
        reference_title: "The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          matriptase-2(MASK) shows no cleavage activity and the human mutant only
          partial cleavage capacity
        explanation: >-
          The graded cleavage result that this readout records.
    evidence:
    - reference: PMID:18976966
      reference_title: "The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here we confirm the inhibitory effect of matriptase-2 on hepcidin
        promoter; we show that matriptase-2 lacking the serine protease domain,
        identified in the anemic Mask mouse (matriptase-2(MASK)), is fully
        inactive and that mutant R774C found in patients with genetic iron
        deficiency has decreased inhibitory activity.
      explanation: >-
        Supports the assay as informative for the cleavage node, with an explicit
        genotype-activity relationship.
differential_diagnoses:
- name: Acquired iron deficiency anemia
  description: >-
    The differential that matters, because it is overwhelmingly more common and
    the two overlap heavily on a full blood count and iron panel. They are not
    strictly indistinguishable: measured head to head, IRIDA patients had lower
    MCV and higher ferritin than iron-deficient controls, both significantly. But
    those are group differences with overlapping distributions, not a rule for an
    individual, and the ferritin difference points the counter-intuitive way -
    higher in the patient with the genetic iron-handling defect.

    The separating test is hepcidin, read against the transferrin saturation:
    suppressed in acquired deficiency, not suppressed in IRIDA. The therapeutic
    trial separates them too, but only after months of ineffective treatment, and
    a genotype-confirmed kindred responsive to oral iron shows even that is not
    absolute.
  distinguishing_features:
  - Hepcidin is low or undetectable in acquired iron deficiency, but within or above the normal range in IRIDA despite an equally low transferrin saturation.
  - Ferritin is significantly higher in IRIDA than in acquired iron deficiency, because the iron is sequestered rather than absent - the opposite of the naive expectation.
  - A haematological response to oral iron argues strongly against IRIDA, but does not exclude it; a genotype-confirmed kindred has been maintained on low-dose oral iron alone.
  evidence:
  - reference: PMID:23729726
    reference_title: "Iron refractory iron deficiency anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to the low/undetectable hepcidin levels observed in acquired
      iron deficiency, in patients with Matriptase-2 deficiency, serum hepcidin
      is inappropriately high for the low iron status
    explanation: >-
      States the discriminating direction of the hepcidin result between the two
      conditions.
- name: Thalassemia trait and other inherited microcytoses
  description: >-
    A congenital microcytic anaemia with a very low MCV in a child invites a
    haemoglobinopathy work-up first, and IRIDA is commonly found only after that
    is negative. The defining study excluded the other inherited causes of
    microcytosis explicitly before implicating TMPRSS6.
  distinguishing_features:
  - Transferrin saturation is low in IRIDA and typically normal in thalassaemia trait.
  - Haemoglobin electrophoresis is normal in IRIDA.
  evidence:
  - reference: PMID:18408718
    reference_title: "Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acquired causes of iron deficiency and other inherited causes of
      microcytosis were rigorously excluded
    explanation: >-
      Records that the entity was delimited by exclusion of exactly this
      differential.
  - reference: PMID:23729726
    reference_title: "Iron refractory iron deficiency anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A challenge for the clinicians and pediatricians is the recognition of the
      disorder among iron deficiency and other microcytic anemias commonly found
      in pediatric patients.
    explanation: >-
      States the recognition problem this differential describes.
discussions:
- discussion_id: irida_two_mechanisms_one_gene
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is matriptase-2's suppression of hepcidin a proteolytic event at all, and if
    not, what does that mean for interpreting a patient's missense variant?
  attaches_to:
  - "pathophysiology#Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin"
  - "pathophysiology#Failure to Suppress Hepcidin Transcription in Iron Deficiency"
  rationale: >-
    Two papers published months apart in 2008 give different answers, and this
    entry curates them as parallel arms rather than resolving a question it has
    no basis to resolve.

    The haemojuvelin account is enzymatic and extracellular: matriptase-2 cleaves
    membrane haemojuvelin, removing a BMP co-receptor that drives HAMP
    transcription. The promoter account is not enzymatic at all - the mouse work
    reports that the cytoplasmic domain mediates Hamp suppression through
    proximal promoter elements, which is not something an ectodomain protease
    activity explains.

    A third result reframes the question rather than settling it between those
    two. Dissecting the proteolytic and non-proteolytic contributions in mice,
    with a protease-dead full-length allele and a truncation lacking the catalytic
    domain, found that the catalytic domain was required to suppress hepcidin -
    but its proteolytic activity was not. Binding, not cutting: the ectodomain
    engaging haemojuvelin, Alk3, ActRIIA and Hfe. A disease-causing allele in that
    same work could still be activated and still failed to suppress hepcidin, and
    what it had lost was its interaction with those partners.

    So the live question is no longer only *which domain*, it is *whether the
    disease is a loss of proteolysis at all*. Note the entry keeps the cleavage
    node rather than deleting it: matriptase-2 does cleave haemojuvelin, the
    reaction is real, and human disease alleles impair it. What is now in doubt is
    whether that cleavage is what the hepcidin suppression runs through.

    The reason this is not academic, and it has sharpened. Every functional assay
    used to classify a novel TMPRSS6 variant reads out cleavage. If suppression is
    a binding function, a variant that cleaves normally in an assay may still be
    pathogenic through lost partner interaction, and a cleavage-normal result is
    not reassurance. The same paper says so in its own conclusion - that
    proteolytic activity is not an appropriate target for modulating MT2
    therapeutically - which is the drug-discovery version of the same point.
  proposed_experiments:
  - experiment_id: exp_irida_domain_separation
    name: Separation-of-function TMPRSS6 alleles in hepatocytes
    description: >-
      Express catalytically dead and cytoplasmic-domain-deleted TMPRSS6 at
      endogenous levels in primary or iPSC-derived human hepatocytes and measure
      HAMP transcription and membrane haemojuvelin independently. If catalytic
      inactivation alone reproduces the full loss of Hamp suppression, the
      cytoplasmic-domain effect is downstream or dispensable.
    would_support:
    - "pathophysiology#Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin"
    supporting_outcome:
    - A catalytically dead allele fails to suppress HAMP and fails to clear membrane haemojuvelin, while the cytoplasmic-domain deletion behaves like wild type.
    would_refute:
    - "pathophysiology#Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin"
    refuting_outcome:
    - A catalytically dead allele still suppresses HAMP normally, placing the operative activity outside the protease domain.
  - experiment_id: exp_irida_binding_versus_cleavage_variant_panel
    name: Partner-binding assay alongside cleavage for a panel of TMPRSS6 variants
    description: >-
      Assay a panel of reported IRIDA missense variants for both haemojuvelin
      cleavage and ectodomain binding to haemojuvelin, ALK3, ACTRIIA and HFE, and
      test which readout better predicts hepcidin suppression. If binding predicts
      and cleavage does not, the standard functional assay used in variant
      classification is measuring the wrong thing.
    would_support:
    - "pathophysiology#Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin"
    supporting_outcome:
    - Cleavage capacity predicts hepcidin suppression across the panel at least as well as partner binding does.
    would_refute:
    - "pathophysiology#Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin"
    refuting_outcome:
    - Variants that cleave haemojuvelin normally but bind partners poorly fail to suppress hepcidin, showing the disease runs through binding rather than proteolysis.
  evidence:
  - reference: PMID:32384154
    reference_title: "The ectodomain of matriptase-2 plays an important nonproteolytic role in suppressing hepcidin expression in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Studies of the protease-dead full-length Mt2 (Mt2S762A) and the truncated
      Mt2 that lacks the catalytic domain (Mt2mask) indicate that the catalytic
      domain, but not its proteolytic activity, was required for Mt2 to suppress
      hepcidin expression.
    explanation: >-
      The separation-of-function result that reframes the question: domain
      required, activity not.
  - reference: PMID:32384154
    reference_title: "The ectodomain of matriptase-2 plays an important nonproteolytic role in suppressing hepcidin expression in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Coimmunoprecipitation analysis revealed that Mt2I286F, but not Mt2S762A, had
      reduced interactions with Hjv, ActRIIA, and Hfe.
    explanation: >-
      Ties a disease-causing allele's failure to lost partner binding rather than
      to lost catalysis, which is what makes the variant-interpretation point
      concrete rather than theoretical.
  - reference: PMID:32384154
    reference_title: "The ectodomain of matriptase-2 plays an important nonproteolytic role in suppressing hepcidin expression in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      these observations support the idea that the substrate interaction with Mt2
      plays a determinant role and suggest that the proteolytic activity is not an
      appropriate target to modulate the function of MT2 for clinical applications
    explanation: >-
      The authors' own conclusion, including its therapeutic corollary.
- discussion_id: irida_hepcidin_assay_standardisation
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Can the diagnostic hepcidin measurement be interpreted across laboratories,
    and what is the decision rule?
  attaches_to:
  - "biochemical#Serum hepcidin"
  - "phenotypes#Hepcidin Not Suppressed Despite Iron Deficiency"
  rationale: >-
    A decision rule exists, it performs extremely well, and it is not yet safe to
    treat as a general-purpose test. Those three things are all true and the
    entry curates the rule in `definitions` rather than in prose so the caveats
    travel with it.

    The rule is the transferrin-saturation-to-hepcidin ratio, below 5.6 %/nM, and
    in its derivation study it separated 20 IRIDA patients from 39 iron-deficient
    controls with an area under the curve of 1.000 - perfect separation, sensitivity
    and specificity both 100%. That is a stronger result than this differential
    usually gets.

    What is not settled is whether the number transfers. Three things about the
    derivation constrain it. Hepcidin was measured by standardised isotope-dilution
    mass spectrometry, and the cut-off is expressed in nM against that method;
    routine hepcidin immunoassays are not calibrated to it, so 5.6 %/nM is not
    portable to another laboratory's units without recalibration. The controls were
    selected to exclude recent iron therapy and CRP of 10.0 mg/L or above, which
    removes the two commonest confounders in exactly the population where the test
    would be used. And with an AUC of 1.000 in 59 people, the confidence intervals
    are what carry the information, not the point estimate: the authors report
    them as 84-100% and 91-100% and say the observations warrant further
    exploration in a broader population.

    This is why `reference_ranges` on the hepcidin biomarker is still empty. A
    single-analyte interval is the wrong object here - the informative quantity is
    the ratio, and the ratio's threshold is method-bound.
  proposed_experiments:
  - experiment_id: exp_irida_hepcidin_ratio_external_validation
    name: External validation of the TSAT/hepcidin ratio in an unselected population
    description: >-
      Apply the 5.6 %/nM threshold prospectively in consecutive patients presenting
      with iron deficiency anaemia in routine practice - without excluding recent
      iron therapy or mild inflammation - with TMPRSS6 sequencing as the reference
      standard, and report the operating characteristics alongside a
      cross-calibration of the local hepcidin assay against isotope-dilution mass
      spectrometry.
    would_support:
    - "definitions#Transferrin saturation to hepcidin ratio"
    supporting_outcome:
    - The published threshold retains a useful positive predictive value in consecutive unselected patients after assay cross-calibration.
    would_refute:
    - "definitions#Transferrin saturation to hepcidin ratio"
    refuting_outcome:
    - Discrimination degrades substantially once recent iron therapy and mild inflammation are no longer exclusions, or the threshold shifts materially between hepcidin methods.
- discussion_id: irida_neogenin_liver_versus_cell_line
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does matriptase-2 cleave its partners in the liver the way it does in cultured
    hepatoma cells, and which system should a variant's functional assay be run in?
  attaches_to:
  - "pathophysiology#Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin"
  rationale: >-
    Nearly all the functional evidence for this disease is transfected-cell
    biochemistry, and there is now a direct demonstration that at least one of
    those cell-line results does not hold in vivo.

    Matriptase-2 cleaves neogenin and sharply reduces neogenin levels in cultured
    hepatoma cells. In mouse liver it does the opposite - it stabilises neogenin -
    and matriptase-2's suppression of hepcidin turns out to require neogenin to be
    present. The same protease, the same partner, opposite directions in the two
    systems.

    That is a `HUMAN_MODEL_MISMATCH` rather than a `KNOWLEDGE_GAP` in the strict
    sense used here: the evidence exists and is good, and what is uncertain is
    which system's answer describes a patient's hepatocyte. The practical stake is
    variant interpretation. A novel TMPRSS6 missense variant is currently assessed
    by exactly the transfected-cell cleavage assay whose fidelity this result puts
    in question, and a variant that cleaves normally in a hepatoma line is not
    thereby shown to be benign.

    Note the mismatch here is model-to-model, mouse liver against human cell line,
    with the human hepatocyte unobserved in both. That makes it a weaker claim
    about human biology than the label might suggest, and a stronger one about not
    trusting the cell line alone.
  proposed_experiments:
  - experiment_id: exp_irida_cleavage_assay_system_comparison
    name: Same-allele comparison across hepatoma line, primary hepatocyte and liver
    description: >-
      Run the same panel of IRIDA missense alleles through the haemojuvelin and
      neogenin cleavage assays in a hepatoma line, in primary or iPSC-derived human
      hepatocytes, and in humanised mouse liver, and compare the rank order of
      functional impairment across the three systems. Concordant rank order would
      license continued use of the cheap assay; discordance would say which alleles
      have been misclassified.
    would_support:
    - "pathophysiology#Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin"
    supporting_outcome:
    - Allele impairment ranks the same way in the hepatoma line as in hepatocytes and liver, so the cell-line assay is a valid surrogate.
    would_refute:
    - "pathophysiology#Loss of Matriptase-2 Cleavage of Membrane Hemojuvelin"
    refuting_outcome:
    - Alleles that look severely impaired in the hepatoma line behave normally in hepatocytes or liver, or the reverse.
  evidence:
  - reference: PMID:41534828
    reference_title: "Matriptase-2-mediated suppression of hepatic hepcidin expression in mice requires hepatocyte neogenin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In contrast to the observations that Mt2 cleaves Neo1 and markedly reduces
      Neo1 levels in cultured hepatoma cells, we found that Mt2 stabilizes Neo1
      in murine liver.
    explanation: >-
      The mismatch itself, stated by the authors as an explicit contrast between
      the cultured cell line and the intact liver.
  - reference: PMID:41534828
    reference_title: "Matriptase-2-mediated suppression of hepatic hepcidin expression in mice requires hepatocyte neogenin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Studies in mice suggest that Mt2 suppression of hepcidin relies on the
      presence of Neo1.
    explanation: >-
      Establishes that neogenin is required for the suppression, which is why the
      discrepant neogenin result bears on the disease mechanism rather than being
      an incidental cell-biology difference.
notes: >-
  Scope. This entry covers the Mendelian disease caused by biallelic TMPRSS6
  loss of function. Common TMPRSS6 polymorphisms are robustly associated with
  haemoglobin and iron indices in the general population, but that is a
  quantitative-trait association rather than this disease, and asserting it here
  would blur a monogenic entity into a susceptibility claim.

  On the two hepcidin-related HP bindings. Both the phenotype "Hepcidin Not
  Suppressed Despite Iron Deficiency" and the biochemical marker use
  HP:0031877 "Elevated circulating hepcidin concentration". HPO has no term for
  hepcidin that is inappropriately high for iron status, which is what the
  disease actually shows, and HP:0031877 is the nearest true statement rather
  than an exact one. The distinction is carried in preferred_term, the
  descriptions, and the assay discussion. A future curator should not "improve"
  this by binding to a term implying an absolute elevation that patients
  frequently do not have.

  On GeneReviews. There is no GeneReviews chapter for IRIDA or for TMPRSS6 - a
  PubMed search of `GeneReviews[Book] OR GeneReviews[Title]` against both terms
  returns nothing. PMID:25064705 is a Hematol Oncol Clin North Am review and
  should not be mistaken for one.

  Not curated for want of quotable evidence in the sources fetched here:
  numeric haematological values from the defining cohort's Table 1 (a table this
  cache renders as prose, so quoting a cell would be unsafe), the natural
  history into adulthood, and pregnancy management.

  Provenance. The entry was built from primary literature; an OpenScientist deep
  research report was run alongside it and is committed as
  `research/IRIDA_Syndrome-deep-research-openscientist.md`. Four of the six
  references added in the second pass - the TSAT/hepcidin ratio study, the
  TMPRSS6 variant functional series, the oral-iron-plus-ascorbate cohort, and
  the anti-TMPRSS6 antibody trial - were leads the report surfaced and this
  curator did not have. Each was verified against PubMed and fetched through
  `just fetch-reference` before use; none was taken from the report's own
  quotation of it. Two of the report's leads changed a conclusion rather than
  adding detail: the ratio study contradicted a draft claim that no validated
  decision rule existed, and the antibody trial supplied human causal evidence
  the entry previously lacked.

📚

References & Deep Research

References

13

PMID:18408718

Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA).

No top-level findings curated for this source.

PMID:18451267

The serine protease TMPRSS6 is required to sense iron deficiency.

No top-level findings curated for this source.

PMID:18976966

The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin.

No top-level findings curated for this source.

PMID:23729726

Iron refractory iron deficiency anemia.

No top-level findings curated for this source.

PMID:25064705

Iron-refractory iron deficiency anemia (IRIDA).

No top-level findings curated for this source.

PMID:25156943

Functional and clinical impact of novel TMPRSS6 variants in iron-refractory iron-deficiency anemia patients and genotype-phenotype studies.

No top-level findings curated for this source.

PMID:35163840

Transferrin Saturation/Hepcidin Ratio Discriminates TMPRSS6-Related Iron Refractory Iron Deficiency Anemia from Patients with Multi-Causal Iron Deficiency Anemia.

No top-level findings curated for this source.

PMID:42053460

A Phase 1 Randomized, Double-Blind, Placebo-Controlled Single and Multiple Ascending Dose Study of DISC-3405, a Novel Recombinant Humanized Monoclonal Antibody Targeting TMPRSS6, in Adult Healthy Volunteers.

No top-level findings curated for this source.

PMID:41534828

Matriptase-2-mediated suppression of hepatic hepcidin expression in mice requires hepatocyte neogenin.

No top-level findings curated for this source.

PMID:30594846

Favourable improvement in haematological parameters in response to oral iron and vitamin C combination in children with Iron Refractory Iron Deficiency Anemia (IRIDA) phenotype.

No top-level findings curated for this source.

PMID:32384154

The ectodomain of matriptase-2 plays an important nonproteolytic role in suppressing hepcidin expression in mice.

No top-level findings curated for this source.

PMID:23319530

Iron refractory iron deficiency anemia: presentation with hyperferritinemia and response to oral iron therapy.

No top-level findings curated for this source.

PMID:36261087

TMPRSS6 gene mutations in six Saudi families with iron refractory iron deficiency anemia.

No top-level findings curated for this source.

Deep Research

1

OpenScientist ▸

IRIDA Syndrome (Iron-Refractory Iron Deficiency Anemia): Comprehensive Disease Characteristics Report

openscientist-autonomous 16 citations 2026-08-29T11:44:55.007964

IRIDA Syndrome (Iron-Refractory Iron Deficiency Anemia): Comprehensive Disease Characteristics Report

Disease: IRIDA Syndrome | MONDO: MONDO:0008788 | OMIM: 206200 | Orphanet: ORPHA:209981 | Category: Genetic (Autosomal Recessive)

Summary

Iron-Refractory Iron Deficiency Anemia (IRIDA) is a rare Mendelian disorder of systemic iron homeostasis caused by biallelic (homozygous or compound heterozygous) loss-of-function mutations in TMPRSS6, the gene encoding the hepatic type II transmembrane serine protease matriptase-2 (MT2). Under normal physiology, matriptase-2 acts as a negative regulator of the iron-regulatory hormone hepcidin: it dampens BMP/SMAD signaling in hepatocytes, in part by cleaving the co-receptor hemojuvelin (HJV). When matriptase-2 function is lost, hepcidin production becomes inappropriately high relative to the body's iron-depleted state. Elevated hepcidin degrades the iron exporter ferroportin (SLC40A1) on duodenal enterocytes and reticuloendothelial macrophages, simultaneously blocking dietary iron absorption and the recycling of iron from senescent red cells. The result is a lifelong, iron-restricted erythropoiesis producing hypochromic microcytic anemia with a distinctive biochemical signature.

The clinical hallmark that unifies diagnosis and mechanism is the paradoxical combination of profound iron deficiency (very low transferrin saturation, typically <5–10%) with inappropriately normal-to-high serum hepcidin — the opposite of acquired iron deficiency, in which hepcidin is low or undetectable. This single feature explains the disease name: because hepcidin remains high, oral iron is poorly absorbed and the anemia is "refractory" to oral supplementation, responding only slowly and partially to intravenous iron. The disorder is generally benign with normal life expectancy; anemia is moderate (Hb ~6–9 g/dL) and often attenuates with age, though microcytosis and low transferrin saturation persist throughout life.

This report synthesizes 14 confirmed findings across 21 reviewed primary papers into a complete disease-knowledge entry spanning etiology, phenotype, molecular mechanism, protein architecture, epidemiology, diagnostics, prognosis, treatment, prevention, comparative biology, and model organisms. A recurring theme with translational significance is that TMPRSS6 sits at a therapeutic fulcrum: because loss of matriptase-2 raises hepcidin, pharmacologic inhibition of TMPRSS6 (antisense oligonucleotides, siRNA, and anti-matriptase-2 monoclonal antibodies such as RLYB331 and DISC-3405) is being actively developed to raise hepcidin in the opposite clinical setting of iron-overload disorders like β-thalassemia and hemochromatosis.

1. Disease Information

Overview. IRIDA is a hereditary, autosomal-recessive form of iron deficiency anemia that is intrinsically resistant to oral iron therapy. It is a disease of dysregulated iron distribution rather than absolute dietary iron insufficiency: iron is present but cannot be mobilized because hepcidin is inappropriately elevated. As summarized by De Falco et al., "Iron refractory iron deficiency anemia is a hereditary recessive anemia due to a defect in the TMPRSS6 gene encoding Matriptase-2" (PMID: 23729726).

Key identifiers.

Resource	Identifier
MONDO	MONDO:0008788
OMIM	206200 (IRIDA)
Orphanet	ORPHA:209981
Gene (HGNC)	TMPRSS6, HGNC:16517
UniProt	Q8IU80 (matriptase-2)
Chromosomal locus	22q12.3

Synonyms / alternative names. Iron-refractory iron deficiency anemia; IRIDA; iron-refractory IDA; TMPRSS6-related iron deficiency anemia; matriptase-2 deficiency; familial iron deficiency anemia refractory to oral iron.

Nature of information. The knowledge base is derived predominantly from aggregated disease-level resources (OMIM, Orphanet) and individual patient/family case reports and small cohort studies in the primary literature, supplemented by functional in-vitro studies and mouse models. There is no large EHR-derived dataset; the disease's rarity means most evidence comes from published kindreds.

2. Etiology

Primary cause (genetic). IRIDA is a monogenic disorder caused by germline biallelic loss-of-function mutations in TMPRSS6. Finberg et al. first established this in 2008, demonstrating that "iron deficiency anemia refractory to oral iron therapy can be caused by germline mutations in TMPRSS6, which encodes a type II transmembrane serine protease produced by the liver that regulates the expression of the systemic iron regulatory hormone hepcidin" (PMID: 18408718). There is no environmental or infectious cause; the disorder is entirely determined by genotype.

Genetic risk factors. - Causal variants: biallelic pathogenic TMPRSS6 variants (>40 distinct mutations reported, spanning all functional domains of the ectodomain — missense, nonsense, frameshift, and splice-site) (PMID: 23729726). - Modifier / susceptibility loci: common TMPRSS6 polymorphisms — most notably rs855791 (p.V736A / A736V) — modulate iron status and erythrocyte indices in the general population and can act as modifiers of anemia severity in IRIDA families (see Section 4). - Consanguinity substantially increases the risk of homozygous disease; recurrent alleles (e.g., p.V736A in Saudi families, p.W590R in Southern Italy) reflect founder/population effects (PMID: 36261087; PMID: 25156943).

Environmental risk factors. None are causal. However, physiologic states of high iron demand (infancy/rapid growth, menstruation, pregnancy) unmask or worsen the phenotype, making females and young children more symptomatic.

Protective factors. No genetic or environmental protective factors are established for IRIDA itself. In the general (non-IRIDA) population, TMPRSS6 iron-lowering alleles are associated with lower iron status; conversely, higher-hepcidin genotypes track with lower iron availability. No dietary or lifestyle factor prevents the monogenic disease.

Gene–environment interactions. The principal interaction is between the fixed genetic lesion and physiological iron demand: the same genotype produces more overt anemia during growth spurts, menstruation, and pregnancy. Common modifier alleles (rs855791) interact with the rare causal alleles to shift severity.

3. Phenotypes

The core phenotype is a congenital/early-childhood hypochromic microcytic anemia with a characteristic iron-study profile. Onset is typically in the post-natal period, "although in some cases it is only diagnosed in adulthood" (PMID: 23729726).

Phenotype	Type	HPO term	Characteristics	Frequency
Hypochromic microcytic anemia	Lab / clinical	HP:0004840	Congenital/early childhood onset; moderate (Hb ~6–9 g/dL); lifelong, often attenuates with age	Near-universal (defining)
Microcytic anemia	Lab	HP:0001935	Low MCV	Near-universal
Decreased MCV	Lab	HP:0025066	Reduced red cell size; persists lifelong	Near-universal
Decreased serum iron	Lab	HP:0040303	Hypoferremia	Very frequent
Very low transferrin saturation	Lab	(iron studies)	TSAT often <5–10%	Very frequent (hallmark)
Inappropriately normal/high hepcidin	Lab	—	Discriminating biochemical feature	Characteristic
Normal or elevated ferritin	Lab	—	Iron trapped in macrophages; occasionally frank hyperferritinemia	Frequent
Fatigue / reduced exercise tolerance	Symptom	HP:0012378	Chronic iron-deficiency symptom	Common
Pallor	Clinical sign	HP:0000980	Reflects anemia	Common
Growth/developmental impact	Clinical	—	During critical growth windows in childhood	Variable

Severity and progression. Anemia is generally moderate, chronic, and stable-to-improving. Genotype modulates severity: "patients carrying two nonsense mutations present a more severe anemia and microcytosis and higher hepcidin levels than the other patients" (PMID: 25156943).

Atypical presentations. The phenotypic spectrum is broader than classic microcytosis. Siblings have presented with "severe microcytic anemia, hypoferremia, and hyperferritinemia" (PMID: 23319530), and normocytic presentations have been described: "normocytic anemia accompanied by low Hb, normal MCV, low serum iron, low serum ferritin, and normal TIBC" (PMID: 36261087).

Quality-of-life impact. Chronic fatigue and reduced exercise tolerance are the main daily-functioning burdens. In infancy and childhood, iron deficiency during critical developmental windows is the principal concern; one report emphasized that "the proband was symptomatic for IRIDA during a critical phase of growth and development" (PMID: 28447549).

4. Genetic / Molecular Information

Causal gene. TMPRSS6 (transmembrane protease, serine 6), chromosome 22q12.3, HGNC:16517, encoding matriptase-2 (MT2), UniProt Q8IU80. OMIM disease entry 206200.

Protein architecture. Matriptase-2 is an 811-amino-acid type II transmembrane serine protease with a modular ectodomain: - N-terminal cytoplasmic tail - single transmembrane domain - SEA domain - two CUB domains - three LDL-receptor class A (LDLRA) repeats - C-terminal trypsin-like serine protease (catalytic) domain with the His-Asp-Ser catalytic triad

It is synthesized as a zymogen requiring autocatalytic activation and undergoes autocleavage/shedding. "TMPRSS6...encodes a type II transmembrane serine protease produced by the liver" (PMID: 18408718).

Pathogenic variants. More than 40 distinct mutations span all functional domains. Representative variants:

Variant	Type	Notes
p.W590R	Missense	Most frequent mutation in Southern Italy (PMID: 25156943)
p.V736A (rs855791)	Missense	Recurrent in Saudi families; also a common population modifier (PMID: 36261087)
p.G442R, p.E522K/E523K	Missense	Compound-heterozygous atypical hyperferritinemia case
p.T287N	Missense	Functional exception — retains activity in assays
p.I286F (murine analog)	Missense	Activated but functionally compromised in mouse studies
Nonsense / frameshift / splice-site	LoF	Associated with more severe phenotype when biallelic

Variant classification (ACMG/AMP). Established recurrent LoF variants are classified pathogenic/likely pathogenic; monoallelic and novel missense variants may be VUS pending functional data.

Allele frequency. Rare causal alleles are private or population-recurrent. In contrast, the common modifier rs855791 is frequent worldwide and was linked by GWAS to "serum iron (rs855791, combined P = 1.5 x 10(-20)), transferrin saturation (combined P = 2.2 x 10(-23)) and erythrocyte mean cell volume (MCV, combined P = 1.1 x 10(-10))" (PMID: 19820699).

Somatic vs germline. All disease-causing variants are germline.

Functional consequences. Mutations are overwhelmingly loss-of-function. Functional assays show that "all but the p.T287N variant impair matriptase-2 autoproteolytic activation, decrease the ability to cleave membrane HJV and inhibit the HJV-dependent hepcidin activation" (PMID: 25156943). Domain-mapping in mice shows "the stem region of MT2 determines the specificity and efficacy for substrate cleavage" (PMID: 30559294), and that "the catalytic domain, but not its proteolytic activity, was required for Mt2 to suppress hepcidin expression" (PMID: 32384154).

Modifier genes. Common TMPRSS6 variants (rs855791 and others) and possibly TF (transferrin) variants modulate iron indices. In IRIDA families, common modifier alleles fine-tune severity alongside the rare causal alleles.

Epigenetic / chromosomal abnormalities. No epigenetic mechanism or large-scale chromosomal abnormality is implicated; IRIDA is a point-mutation/small-variant disorder.

5. Environmental Information

Environmental factors: None causal. No toxin, radiation, or occupational exposure is implicated.
Lifestyle factors: Dietary iron intake does not cause the disease and cannot cure it (oral iron is poorly absorbed). High-iron-demand states (growth, menstruation, pregnancy) modulate symptom expression.
Infectious agents: Not applicable. IRIDA is non-infectious. (Note: inflammation/infection independently raises hepcidin and can confound differential diagnosis — see Section 10.)

6. Mechanism / Pathophysiology

Causal chain

Biallelic LoF mutation in TMPRSS6
│
▼
Loss / dysfunction of matriptase-2 (MT2) in hepatocytes
│  (fails to autoactivate; cannot cleave membrane hemojuvelin;
│   cannot suppress HJV/NEO1-dependent BMP/SMAD signaling)
▼
Un-dampened BMP/SMAD signaling  →  INAPPROPRIATELY HIGH HEPCIDIN
│
▼
Hepcidin binds & degrades ferroportin (SLC40A1)
│
├─► Duodenal enterocytes: blocked dietary iron ABSORPTION
└─► Splenic/hepatic macrophages: blocked iron RECYCLING
│
▼
Low serum iron, very low transferrin saturation
│
▼
Iron-restricted erythropoiesis in bone marrow
│
▼
Hypochromic microcytic anemia (refractory to oral iron)

Molecular pathway (upstream). Matriptase-2 is a negative regulator of the BMP/SMAD hepcidin-induction pathway. "Transmembrane serine protease 6 (TMPRSS6) suppresses hepcidin via the bone morphogenetic protein/small mothers against decapentaplegic (BMP/SMAD) pathway by cleaving the co-receptor hemojuvelin" (PMID: 42053460). "In vitro experiments on transfected cells suggest that Matriptase-2 cleaves Hemojuvelin, a major regulator of hepcidin expression and that this function is altered in this genetic form of anemia" (PMID: 23729726). MT2 also interacts with additional pathway components including Alk3, ActRIIA, HFE, and neogenin (NEO1); in-vivo mouse work indicates "Mt2 suppression of hepcidin relies on the presence of Neo1" and that MT2 acts "by inhibiting the Neo1/Hjv-induced Bmp-signaling pathway" (PMID: 41534828).

Effector axis (downstream). Hepcidin is "a circulating hormone produced by the liver that inhibits dietary iron absorption and macrophage iron release" (PMID: 21355094). Its excess degrades ferroportin, the sole cellular iron exporter, at the two key gateways: the enterocyte (absorption) and the macrophage (recycling).

Cellular processes / cell types. Iron-restricted erythropoiesis (bone marrow erythroblasts), impaired transepithelial iron transport (duodenal enterocytes), impaired iron recycling (reticuloendothelial macrophages).

Suggested GO / CL terms. GO:0006879 (intracellular iron ion homeostasis), GO:0060586 (multicellular organismal iron ion homeostasis), GO:0030509 (BMP signaling pathway), GO:0006508 (proteolysis). Cell types: CL:0000182 (hepatocyte), CL:0000584 (enterocyte), CL:0000235 (macrophage), CL:0000765 (erythroblast).

Metabolic / biochemical abnormality. The core defect is a protease loss-of-function producing hormonal (hepcidin) dysregulation of systemic iron trafficking — not an enzyme-deficiency metabolic block in a biosynthetic pathway.

Immune involvement. None primary. IRIDA is not autoimmune or immunodeficient; however, hepcidin is the shared node with anemia of inflammation, which is IL-6/inflammation-driven.

Molecular profiling. In-vitro functional studies (transfected cell cleavage assays) and mouse transcriptional readouts of hepatic hepcidin (Hamp) are the principal profiling data. No large human transcriptomic/proteomic/metabolomic dataset is established for IRIDA specifically.

7. Anatomical Structures Affected

Site of the primary defect. The liver (hepatocytes) — matriptase-2 is "produced by the liver" (PMID: 18408718). UBERON:0002107 (liver); CL:0000182 (hepatocyte).

Effector sites (secondary). - Duodenum / small intestine — enterocyte iron absorption blocked. UBERON:0002114 (duodenum); CL:0000584 (enterocyte). - Spleen / reticuloendothelial system — macrophage iron recycling blocked. UBERON:0002106 (spleen); CL:0000235 (macrophage). - Bone marrow — iron-restricted erythropoiesis. UBERON:0002371 (bone marrow); CL:0000765 (erythroblast).

Body systems. Hematopoietic/hematologic (primary clinical manifestation) and hepatobiliary/digestive (site of defect and iron absorption).

Subcellular level. Matriptase-2 is a plasma-membrane-anchored protein (GO:0005886, plasma membrane); its cytoplasmic tail faces the cytosol and the catalytic ectodomain the extracellular space. Ferroportin resides at the basolateral/plasma membrane of effector cells.

Localization / lateralization. The disease is systemic and bilateral/non-lateralized; there is no anatomical asymmetry.

8. Temporal Development

Onset: Congenital/early post-natal, though sometimes first recognized in adulthood — "The anemia appears in the post-natal period, although in some cases it is only diagnosed in adulthood" (PMID: 23729726). Onset pattern is chronic/insidious.
Progression: Slow, chronic, and generally stable-to-improving. Hemoglobin frequently improves with age even as microcytosis and low transferrin saturation persist. Not staged like a neoplastic disease.
Disease course: Lifelong (chronic) but non-progressive in a degenerative sense; severity is set largely by genotype (biallelic nonsense = more severe).
Critical periods: Infancy/childhood growth phases and other high-iron-demand windows (menstruation, pregnancy) are periods of greatest vulnerability and the key windows for intervention (PMID: 28447549).
Remission: No true remission; partial correction is achievable with parenteral iron, and spontaneous improvement of hemoglobin with age is common.

9. Inheritance and Population

Inheritance. Autosomal recessive; affected individuals are homozygous or compound heterozygous for TMPRSS6 pathogenic variants (PMID: 23729726). Sibling recurrence risk is 25%.

Epidemiology. Rare; fewer than a few hundred families reported worldwide. Exact prevalence is undetermined and likely underestimated due to under-recognition among common microcytic anemias. Orphanet ORPHA:209981.

Penetrance / expressivity. Biallelic pathogenic genotypes are essentially fully penetrant for the biochemical phenotype (microcytosis, low TSAT), with variable expressivity of anemia severity governed by genotype and modifier alleles. Monoallelic (single heterozygous) variants may contribute to milder/atypical iron deficiency with incomplete penetrance still under study.

Founder effects / population recurrence. Population-recurrent alleles include p.W590R ("the most frequent mutation in Southern Italy," PMID: 25156943) and p.V736A, which "was found in all examined Saudi families with IRIDA" (PMID: 36261087). Consanguinity raises homozygous-case frequency.

Demographics. Reported across European, Middle Eastern, Asian, and North African populations. Both sexes affected; no strong sex predilection, though females tend to be more symptomatic due to higher iron demands. No genetic anticipation (not a repeat-expansion disorder).

10. Diagnostics

Laboratory workup. 1. CBC with indices: low Hb, low MCV, low MCH (hypochromic microcytic pattern). 2. Iron studies: low serum iron, very low transferrin saturation (often <5–10%), normal-to-high ferritin. 3. Serum hepcidin: inappropriately normal/high — the discriminating biomarker. 4. Molecular confirmation: TMPRSS6 sequencing.

Key discriminating biomarker. "In contrast to the low/undetectable hepcidin levels observed in acquired iron deficiency, in patients with Matriptase-2 deficiency, serum hepcidin is inappropriately high for the low iron status and accounts for the absent/delayed response to oral iron treatment" (PMID: 23729726). The transferrin saturation/hepcidin ratio operationalizes this discrimination: van der Staaij et al. showed the "Transferrin Saturation/Hepcidin Ratio Discriminates" pathogenic TMPRSS6-related iron deficiency from other causes (PMID: 35163840).

Genetic testing. Single-gene TMPRSS6 sequencing, targeted iron/anemia gene panels, or whole-exome sequencing for atypical cases. WES has resolved unusual presentations: "whole exome sequencing can be used as a diagnostic tool and greatly facilitate the elucidation of the genetic basis of unusual clinical presentations" (PMID: 23319530).

Differential diagnosis.

Condition	Distinguishing feature
Nutritional/blood-loss iron deficiency	Hepcidin low; responds to oral iron
β-/α-thalassemia trait	Normal/high iron; elevated HbA2 (β) or globin imbalance; high-normal RBC count
Anemia of chronic disease/inflammation	Hepcidin high but IL-6/CRP elevated; inflammatory context
DMT1 (SLC11A2) defect, atransferrinemia, aceruloplasminemia, sideroblastic anemias	Distinct iron-study patterns / systemic features

"A challenge for the clinicians and pediatricians is the recognition of the disorder among iron deficiency and other microcytic anemias commonly found in pediatric patients" (PMID: 23729726).

Screening. No population/newborn screening exists. Cascade genetic testing of relatives is appropriate once a proband's variants are known.

11. Outcome / Prognosis

Survival/mortality: Benign; normal life expectancy. No disease-specific mortality is reported.
Disease course: Lifelong, moderate, chronic anemia that "shows a slow response to intravenous iron injections and partial correction of the anemia" (PMID: 23729726); hemoglobin often improves with age.
Morbidity: Chronic fatigue, reduced exercise tolerance, and — in infancy/childhood — potential growth and neurodevelopmental impact during critical windows (PMID: 28447549).
Prognostic factors: Genotype is prognostic — biallelic nonsense mutations predict more severe, less-responsive anemia with higher hepcidin (PMID: 25156943). Treatment response is itself a prognostic indicator.

12. Treatment

First principle: By definition IRIDA is refractory to oral iron because absorption is hepcidin-blocked.

Modality	Evidence	NCIT concept
Intravenous (parenteral) iron	Standard of care; slow, partial correction (PMID: 23729726)	Iron supplement therapy (parenteral)
Oral iron + vitamin C	In a pediatric IRIDA-phenotype cohort, "complete response in majority (6/7 = 86%) with >2 g/dL rise in Hb along with significant improvement of other iron related indices" (PMID: 30594846)	Ferrous salt + ascorbic acid
Supportive care	Monitor growth/development in children; manage fatigue	Supportive care

Pharmacogenomics. Response is genotype-dependent (nonsense/nonsense = poorest response). No conventional drug-metabolism pharmacogenomic markers apply.

Emerging / experimental. There is no approved IRIDA-specific targeted therapy. Conceptually, a hepcidin-lowering agent (e.g., anti-hepcidin or BMP-pathway antagonist) would be mechanistically rational, but the active TMPRSS6 drug pipeline is aimed at the opposite problem (raising hepcidin in iron overload — see Section 13).

13. Prevention

Primary prevention: Not applicable — the disorder is monogenic with no environmental/infectious trigger.
Secondary/tertiary prevention: Early molecular diagnosis and timely iron repletion (parenteral, or oral iron + vitamin C) to prevent developmental sequelae, especially during childhood growth windows.
Genetic counseling (central): Autosomal-recessive 25% sibling recurrence risk; carrier/cascade testing of relatives; reproductive options (prenatal and preimplantation genetic testing) where the family's TMPRSS6 variants are defined.
Screening: No population or newborn screening. Cascade testing within affected families is the practical preventive tool.

14. Other Species / Natural Disease

Taxonomy / orthologs: TMPRSS6 is evolutionarily conserved. Mouse ortholog Tmprss6 (NCBI Gene 71753; Mus musculus, NCBI:txid10090).
Natural disease: No well-documented naturally occurring companion-animal or wildlife IRIDA in OMIA; IRIDA is essentially a human-defined disorder recapitulated in engineered rodents.
Comparative biology: The hepcidin–ferroportin axis and matriptase-2's suppressive role are conserved between human and mouse; Tmprss6 disruption in mice reproduces the human iron-deficiency phenotype (see Section 15).
Zoonotic potential: None (non-infectious genetic disease).

15. Model Organisms

Mouse is the principal model. Two complementary genetic models recapitulate IRIDA: - Tmprss6 knockout and the ENU-derived "mask" mouse (Mt2^mask, lacking the catalytic domain), which develop elevated hepcidin, systemic iron deficiency, and microcytic anemia. - Modifier/therapeutic-target validation: Finberg et al. showed "heterozygous loss of Tmprss6 in Hfe(-/-) mice reduced systemic iron overload, whereas homozygous loss caused systemic iron deficiency and elevated hepatic expression of hepcidin" (PMID: 21355094) — establishing Tmprss6 as a genetic modifier and therapeutic target.

Domain-function dissection in mice. - "The catalytic domain, but not its proteolytic activity, was required for Mt2 to suppress hepcidin expression" (PMID: 32384154). - "The stem region of MT2 determines the specificity and efficacy for substrate cleavage" (PMID: 30559294). - Hepatocyte neogenin is required: "Mt2 suppression of hepcidin relies on the presence of Neo1" (PMID: 41534828).

Phenotype recapitulation: Excellent for the core biochemical and hematologic phenotype (high hepcidin, low iron, microcytic anemia). Limitations: models are engineered rather than spontaneous; species differences in iron demand and lifespan; human genotype–phenotype heterogeneity (e.g., specific missense alleles) not fully captured by null models.

Translational fulcrum — the "mirror-image" drug pipeline. Because loss of matriptase-2 raises hepcidin, TMPRSS6 inhibition is being developed to raise hepcidin in iron-overload disease: - Antisense oligonucleotides: "antisense oligonucleotide-mediated inhibition of TMPRSS6, an upstream regulator of hepcidin" (PMID: 24589273). - Anti-matriptase-2 antibody RLYB331: "we tested a fully human anti-matriptase-2 antibody, RLYB331, which blocks the protease activity of matriptase-2" (PMID: 38241484). - Clinical-stage antibody DISC-3405: "a novel humanized monoclonal antibody that enhances hepcidin expression by inhibiting TMPRSS6"; in Phase 1 it "increased hepcidin-25 and reduced serum iron and transferrin saturation across dose levels" (PMID: 42053460).

These programs validate TMPRSS6/matriptase-2 biology pharmacologically and, by inference, confirm the IRIDA mechanism in reverse.

Mechanistic Model / Interpretation

IRIDA is best understood as a hormonal iron-trafficking disease driven by a single upstream protease loss. The elegance of the model is that one molecular event (loss of matriptase-2) propagates deterministically to the clinical picture:

GENE            PROTEIN            SIGNALING           HORMONE        EFFECTOR            PHENOTYPE
TMPRSS6  ──►  matriptase-2  ──►  BMP/SMAD (via     ──► hepcidin  ──► ferroportin    ──►  hypochromic
(LoF, AR)     (loss of           HJV/NEO1              (HIGH,         degradation on       microcytic
      function)          cleavage/            inappropriate)  enterocytes +        anemia,
                 inhibition lost)                     macrophages          low TSAT,
                                                                           oral-iron
                                                                           refractory

Everything downstream of hepcidin is shared with normal iron physiology; the disease-specific lesion is the failure to restrain hepcidin when iron is low. This explains three otherwise puzzling clinical features simultaneously: (1) why oral iron fails (absorption is blocked at the enterocyte), (2) why ferritin can be normal/high despite anemia (iron is trapped in macrophages), and (3) why the disease is diagnostically distinguishable from every other microcytic anemia by hepcidin measurement.

The upstream vs downstream hierarchy also clarifies therapeutic logic: the ideal IRIDA therapy would act upstream (restore matriptase-2 function or lower hepcidin), whereas current management acts far downstream by force-feeding iron parenterally past the enterocyte block. Conversely, the same axis run in reverse (inhibit TMPRSS6 → raise hepcidin) is a validated strategy for iron-overload diseases — a striking example of one gene being both the cause of one disease and the drug target for its mirror image.

Evidence Base

PMID	Title (abbrev.)	Role in this report
18408718	Mutations in TMPRSS6 cause IRIDA	Foundational — establishes causal gene and matriptase-2's hepcidin-regulating role
23729726	Iron refractory iron deficiency anemia (review)	Core clinical/mechanistic reference: inheritance, hallmarks, hepcidin discriminator, treatment, DDx
25156943	Functional and clinical impact of novel TMPRSS6 variants	Functional LoF evidence; genotype–phenotype (nonsense = severe); p.W590R
42053460	Phase 1 DISC-3405 anti-TMPRSS6	BMP/SMAD-HJV mechanism statement; target validation
19820699	Common TMPRSS6 variants & iron status (GWAS)	Modifier variant rs855791 effects on iron/MCV
36261087	TMPRSS6 mutations in Saudi families	Founder allele p.V736A; atypical normocytic presentation
21355094	Tmprss6 modifier of Hfe in mice	Mouse model; effector definition (enterocyte + macrophage)
23319530	IRIDA with hyperferritinemia; WES	Atypical hyperferritinemia; WES diagnostic utility
30594846	Oral iron + vitamin C in IRIDA phenotype	86% response — emerging oral therapy
35163840	TSAT/Hepcidin ratio discriminates	Diagnostic biomarker ratio
32384154	Ectodomain nonproteolytic role	Catalytic-domain requirement (mouse)
30559294	Catalytic/stem/TM portions required	Domain structure-function
41534828	MT2 requires hepatocyte neogenin	NEO1 dependency in vivo
24589273	Modulation of hepcidin — ASO	Mirror-image therapy (ASO)
38241484	Anti-matriptase-2 antibody RLYB331	Mirror-image therapy (antibody) in β-thalassemic mice
28447549	Child with complex TMPRSS6 genotype	Critical growth-period vulnerability

Concordance: All reviewed papers point to a consistent single-gene, single-mechanism model. No paper challenges the central TMPRSS6→hepcidin causal chain; heterogeneity is confined to phenotypic spectrum (occasional hyperferritinemia or normocytosis) and treatment response (genotype-dependent).

Limitations and Knowledge Gaps

Prevalence is undetermined. No population-level incidence/prevalence figures exist; the disease is likely under-diagnosed among common microcytic anemias.
No human -omics datasets. There are no established large-scale transcriptomic/proteomic/metabolomic profiles specific to IRIDA patients; mechanism rests on in-vitro assays and mouse models.
Monoallelic variant significance is unresolved. The pathogenic contribution and penetrance of single heterozygous TMPRSS6 variants to milder/atypical iron deficiency remain under study.
No IRIDA-specific approved therapy. Current care is symptomatic (parenteral iron); the mechanistically ideal hepcidin-lowering therapeutic has not been developed for IRIDA (all TMPRSS6 drugs target the opposite direction).
Genotype–phenotype rules are incomplete. Beyond the nonsense/nonsense = severe correlation, predictive rules for individual missense alleles and modifier interactions are not fully defined.
Long-term neurodevelopmental outcomes of childhood iron deficiency in IRIDA are not rigorously quantified.

Proposed Follow-up Experiments / Actions

Establish a natural-history registry to quantify prevalence, sex ratio, age-dependent hemoglobin trajectory, and neurodevelopmental outcomes.
Prospective trial of oral iron + vitamin C vs IV iron in molecularly confirmed IRIDA, powered on hemoglobin response and quality of life, to validate the 86% pediatric response signal (PMID: 30594846).
Standardize the TSAT/hepcidin ratio as a first-line discriminating test with defined cutoffs across laboratories (PMID: 35163840).
Functional classification pipeline (cell-based autoactivation + HJV-cleavage + hepcidin-suppression assays, per PMID: 25156943) to resolve VUS and monoallelic variants toward ACMG reclassification.
Explore hepcidin-lowering therapeutics for IRIDA (anti-hepcidin antibodies, BMP-pathway antagonists, or ferroportin stabilizers) — the mechanistically rational but unexploited direction.
Cascade genetic counseling and carrier screening in consanguineous populations harboring founder alleles (p.V736A, p.W590R).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	16
Resolved	16
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	32
Quoted claims found in source	31
Quoted claims not found in source	1
References weighed for topical relevance	16
On topic	12
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMID:25156943 (abstract only): "all but the p.T287N variant impair matriptase-2 autoproteolytic activation, decrease the ability to cleave membrane HJV and inhibit the HJV-dependent hepcidin activation"
closest text in source: "All but the p.T287N variant impair matriptase-2 autoproteotylic activation, decrease the ability to cleave membrane HJV and inhibit the HJV-dependent hepcidin activation"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	22
Resolved	20
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	19
Terms named correctly	11
Terms named as a different term	7
Terms whose name is worth a second look	1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0008788 (2 mentions) - the report calls it "MONDO"; MONDO calls it IRIDA syndrome
HP:0004840 (1 mention) - the report calls it "Lab / clinical"; HP calls it Hypochromic microcytic anemia
HP:0001935 (1 mention) - the report calls it "Lab"; HP calls it Microcytic anemia
HP:0025066 (1 mention) - the report calls it "Lab"; HP calls it Decreased mean corpuscular volume
HP:0040303 (1 mention) - the report calls it "Lab"; HP calls it Decreased circulating iron concentration
HP:0012378 (1 mention) - the report calls it "Symptom"; HP calls it Fatigue
HP:0000980 (1 mention) - the report calls it "Clinical sign"; HP calls it Pallor

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

GO:0060586 (1 mention) - the report calls it "multicellular organismal iron ion homeostasis"; GO calls it multicellular organismal-level iron ion homeostasis, and lists "multicellular organismal iron ion homeostasis" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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IRIDA Syndrome (Iron-Refractory Iron Deficiency Anemia): Comprehensive Disease Characteristics Report

Summary

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Causal chain

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

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Term Validation

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