Microcytic Anemia With Liver Iron Overload

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Mappings

MONDO

MONDO:0008787 microcytic anemia with liver iron overload

👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

Reported patients have been homozygous or compound heterozygous for SLC11A2 variants, with healthy heterozygous carrier parents.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:15459009 SUPPORT Human Clinical

"This homozygous mutation in the ultimate nucleotide of exon 12 codes for a conservative E399D amino acid substitution"

The first reported patient was homozygous for the causative SLC11A2 variant, establishing recessive transmission.

PMID:16160008 SUPPORT Human Clinical

"We report the hematologic phenotype of a child, compound heterozygote for 2 DMT1 mutations, who was affected by severe anemia since birth and showed hepatic iron overload."

Independent patient with biallelic compound heterozygous transmission.

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Discussions and Knowledge Gaps

1

Why do humans with biallelic SLC11A2/DMT1 loss develop hepatic iron overload when the mk mouse and Belgrade rat carrying the analogous G185R mutation are iron-deficient rather than iron-overloaded?

HUMAN MODEL MISMATCH OPEN ahmio1_human_model_hepatic_overload_mismatch

Attached to

pathophysiology#Hepatic Iron Overload via DMT1-Independent Uptake animal_models#Mouse

The erythroid and intestinal iron-transport failure of DMT1 deficiency is faithfully reproduced by the rodent models, but the paradoxical hepatic iron overload that names the human disease is not: the mk mouse and Belgrade rat are iron-deficient. The divergence is mechanistically meaningful because it localises the open question to the hepatic arm - whether a species difference in DMT1-independent hepatic uptake (for example ZIP14-mediated non-transferrin-bound iron entry under high serum iron), in dietary iron handling, or in iatrogenic iron exposure explains why humans load hepatic iron while the analogous rodents do not.

Proposed experiments

Cross-species comparison of DMT1-independent hepatic iron uptake

cross-species model comparison experiment

exp_ahmio1_cross_species_hepatic_iron

Compare hepatic non-transferrin-bound-iron uptake and ZIP14 expression in DMT1-mutant mk mice and Belgrade rats against human AHMIO1 liver tissue under matched high-serum-iron conditions, to determine whether a species difference in the DMT1-independent hepatic route explains the divergent iron-overload phenotype.

Controlled iron loading of DMT1-mutant rodents

model-system iron-loading experiment

exp_ahmio1_iron_loaded_rodent_hepatic

Systematically iron-load DMT1-mutant rodents (as with the reported iron dextran injection in the Belgrade rat) and quantify hepatic iron deposition and its ZIP14 dependence, to test whether the human hepatic overload reflects the DMT1-independent route operating under the high serum iron of untreated or transfused patients.

Show evidence (1 reference)

PMID:15459009 SUPPORT Model Organism

"unlike the animal models of DMT1 mutation, the patient is iron overloaded"

Directly states the human-versus-model divergence in the iron-overload phenotype that this discussion is about.

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Pathophysiology

4

SLC11A2/DMT1 Loss of Function

Biallelic SLC11A2 variants reduce or abolish functional DMT1, the proton-coupled divalent metal transporter that carries ferrous iron across membranes. Different alleles act by different molecular routes - defective protein processing and endoplasmic-reticulum retention (R416C), lysosomal mis-accumulation and degradation (G75R), or exon skipping that leaves only a small amount of functional transporter (E399D) - but all converge on quantitatively reduced DMT1 activity.

SLC11A2 hgnc:10908

iron ion transmembrane transporter activity GO:0005381 ↓ DECREASED

Downstream

Impaired Erythroid Transferrin-Cycle Iron Utilization DMT1 releases transferrin-cycle iron from recycling endosomes into the cytosol of erythroid precursors; its loss blocks this erythroid iron use.

Impaired Duodenal Iron Absorption DMT1 mediates apical (brush-border) iron uptake in duodenal enterocytes, so its loss impairs dietary iron absorption.

Hepatic Iron Overload via DMT1-Independent Uptake Liver iron uptake does not require DMT1, so its loss does not protect the liver; hepatic iron loading proceeds through other pathways.

Show evidence (3 references)

PMID:15459009 SUPPORT Human Clinical

"We report here the first human mutation of DMT1 identified in a female with severe hypochromic microcytic anemia and iron overload."

Establishes DMT1/SLC11A2 loss of function as the cause of the human disease.

PMID:16584902 SUPPORT In Vitro

"We propose that DMT1(C1246T) (R416C) represents a complete loss-of-function, and that a quantitative reduction in DMT1 expression is the cause of the microcytic anemia and iron overload in the patient."

Functional characterisation showing a disease allele is a complete loss-of-function producing a quantitative reduction in transporter.

PMID:16023393 SUPPORT In Vitro

"This indicates that DMT1G1285C is not a complete loss of function but rather that a modest amount of active DMT1 is produced in this patient."

Supports the node's E399D claim that the exon-12 allele leaves only a small amount of functional transporter rather than abolishing it, from functional assays of the mutant expressed in LLC-PK1 cells.

Impaired Erythroid Transferrin-Cycle Iron Utilization

In erythroid precursors, iron delivered by transferrin is internalised through the transferrin-receptor cycle and must be exported from the recycling endosome into the cytosol by DMT1 to reach the mitochondrion for haem synthesis. Loss of DMT1 leaves iron trapped in the endosome, starving haemoglobin synthesis despite adequate whole-body iron.

erythroblast CL:0000765

iron ion transmembrane transport GO:0034755 ↓ DECREASED

recycling endosome GO:0055037

Animal models

mk mouse (Slc11a2 G185R) Mouse recapitulates The mk mouse reproduces defective erythroid iron utilization and the resulting hypochromic microcytic anemia.

Belgrade rat (Slc11a2 G185R) Rat recapitulates The Belgrade rat reproduces the severe congenital microcytic anemia and defective erythroid iron use of DMT1 deficiency.

Downstream

Microcytic anemia Failure of erythroid iron utilization blocks haemoglobin synthesis, producing hypochromic microcytic anemia.

Elevated circulating iron concentration Iron delivered to erythroid precursors but not utilized for haemoglobin synthesis is left unconsumed, so serum iron rises even as red-cell iron falls.

Elevated transferrin saturation With circulating iron rising and iron-binding capacity normal, transferrin saturation increases - the iron-overloaded serum profile that separates the disorder from iron-deficiency anemia.

Show evidence (1 reference)

PMID:35457224 SUPPORT Human Clinical

"DMT1 has a vital role in iron homeostasis by mediating iron uptake in the intestine and kidneys and by recovering iron from recycling endosomes after transferrin endocytosis."

Establishes the recycling-endosome iron-recovery step that is lost in erythroid precursors.

Impaired Duodenal Iron Absorption

DMT1 imports dietary ferrous iron across the apical brush-border membrane of duodenal enterocytes. Its loss impairs intestinal iron absorption; in humans, however, this is partly bypassed by up-regulation of other absorptive pathways, so intestinal loss alone does not produce iron deficiency.

enterocyte CL:0000584

iron ion transmembrane transport GO:0034755 ↓ DECREASED

brush border membrane GO:0031526

Show evidence (1 reference)

PMID:15459009 SUPPORT Human Clinical

"Divalent metal transporter 1 (DMT1) is a transmembrane protein crucial for duodenal iron absorption and erythroid iron transport."

Establishes the duodenal iron-absorption function impaired by DMT1 loss.

Hepatic Iron Overload via DMT1-Independent Uptake

Because hepatocyte iron uptake does not require DMT1, and serum iron and transferrin saturation are high, the liver continues to acquire iron through DMT1-independent routes - non-transferrin-bound iron entering hepatocytes probably via the ZIP14 transporter. Transfusion and oral iron given for the anemia further exacerbate this loading.

hepatocyte CL:0000182

Animal models

mk mouse (Slc11a2 G185R) Mouse fails to recapitulate The rodent DMT1-mutant models are iron-deficient, not iron-overloaded, so they do not spontaneously reproduce the hepatic iron loading that defines the human disease.

Belgrade rat (Slc11a2 G185R) Rat partially recapitulates Under exogenous iron loading the Belgrade rat deposits iron in the liver despite DMT1 loss, demonstrating the DMT1-independent hepatic uptake route (probably ZIP14) that drives the human hepatic overload.

Downstream

Elevated hepatic iron concentration Continued DMT1-independent hepatic iron acquisition deposits iron in the liver.

Show evidence (1 reference)

PMID:35457224 SUPPORT Model Organism

"This DMT1-independent iron acquisition, in a high serum iron level condition, is performed probably through the ZIP14 transporter"

Names the DMT1-independent hepatic uptake route (ZIP14) operating under high serum iron. Cited as MODEL_ORGANISM because this sentence describes the Belgrade rat.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

4

Blood 1

Microcytic anemia Hypochromic microcytic anemia HP:0004840

Onset: CONGENITAL

Show evidence (1 reference)

PMID:19786204 SUPPORT Human Clinical

"This recessively inherited condition appears at birth with severe microcytic anemia."

Establishes the congenital, severe microcytic anemia as the core phenotype.

Digestive 1

Elevated hepatic iron concentration HP:0012465

Show evidence (1 reference)

PMID:19786204 SUPPORT Human Clinical

"Moreover liver iron overload was present and documented in all of the affected patients."

Documents hepatic iron overload across the reported patient series.

Metabolism 2

Elevated circulating iron concentration Increased circulating iron concentration HP:0003452

Show evidence (1 reference)

PMID:19786204 SUPPORT Human Clinical

"high serum iron, normal total iron-binding capacity (TIBC), increased saturation of transferrin (Tf), slightly elevated ferritin, and increased soluble transferrin receptor (sTfR)."

Reports the high serum iron that characterises the biochemical profile.

Elevated transferrin saturation HP:0012463

Show evidence (1 reference)

PMID:19786204 SUPPORT Human Clinical

"increased saturation of transferrin (Tf)"

Reports the increased transferrin saturation in the biochemical profile.

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Genetic Associations

1

SLC11A2 biallelic pathogenic variants (Causative)

Gene: SLC11A2 hgnc:10908 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:15459009 SUPPORT Human Clinical

"We report here the first human mutation of DMT1 identified in a female with severe hypochromic microcytic anemia and iron overload."

The first reported causative SLC11A2/DMT1 genotype.

PMID:16160008 SUPPORT Human Clinical

"The novel mutations were a 3-bp deletion in intron 4 (c.310-3_5del CTT) resulting in a splicing abnormality and a C>T transition at nucleotide 1246(p. R416C)."

An independent biallelic (compound heterozygous) causative genotype.

PMID:21871825 SUPPORT Human Clinical

"the N491S mutation, through its deleterious effect on protein trafficking, contributes together with the G212V mutation to the development of anemia and hepatic iron overload."

A further biallelic genotype (G212V plus N491S) with a trafficking-based mechanism.

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Medical Actions

2

Recombinant erythropoietin

Action: Pharmacotherapy NCIT:C15986

Agent: recombinant erythropoietin NCIT:C477

Platform: Protein replacement

Recombinant erythropoietin is the reported treatment of choice: all described patients responded, with improved haemoglobin. Mean corpuscular volume and mean corpuscular haemoglobin did not change during treatment, so erythropoietin is thought to act by reducing erythroblast apoptosis (relieving ineffective erythropoiesis) rather than by improving erythroid iron utilization, and it may also help mobilise excess hepatic iron.

Target Phenotypes: Hypochromic microcytic anemia HP:0004840

Show evidence (2 references)

PMID:19786204 SUPPORT Human Clinical

"All patients appeared to respond to erythropoietin (Epo) administration."

Reports the erythropoietin response across the affected patients.

PMID:19786204 SUPPORT Human Clinical

"it was concluded that Epo did not improve iron utilization of the erythroblasts but likely reduced the degree or intensity of apoptosis, affecting erythropoiesis."

States the proposed mechanism of erythropoietin benefit (reduced apoptosis, not improved iron use).

Avoidance of iron supplementation and routine transfusion

Action: Supportive Care NCIT:C15747

Platform: Other

Oral iron and transfusion - the default management of a microcytic anemia - are counterproductive here because hepatic iron uptake is DMT1-independent, so added iron worsens the overload. Recognising the disease early to avoid these treatments is a management priority.

Target Phenotypes: Elevated hepatic iron concentration HP:0012465

Show evidence (1 reference)

PMID:35457224 SUPPORT Human Clinical

"we suggest that liver iron accumulation observed in some AHMIO1 patients might be exacerbated by transfusions and/or oral iron supplements, the gold standard treatments for general anemic patients."

Directly supports avoiding iron supplementation and transfusion because they aggravate the iron overload.

🌍

Environmental Factors

1

Iatrogenic iron loading from transfusion and oral iron supplementation

Transfusion and oral iron - the default management of a microcytic anemia - add iron that the DMT1-independent hepatic uptake route deposits in the liver, aggravating the overload; this is why early recognition to avoid these treatments is a management priority.

Show evidence (1 reference)

PMID:35457224 SUPPORT Human Clinical

"we suggest that liver iron accumulation observed in some AHMIO1 patients might be exacerbated by transfusions and/or oral iron supplements, the gold standard treatments for general anemic patients."

Names iatrogenic transfusion and oral iron as exacerbators of the hepatic iron overload.

Mechanism Target:

EXACERBATES Hepatic Iron Overload via DMT1-Independent Uptake — Exogenously administered iron feeds the DMT1-independent hepatic uptake route, worsening hepatic iron loading.

Show evidence (1 reference)

PMID:35457224 SUPPORT Human Clinical

"Therefore, we suggest that liver iron accumulation observed in some AHMIO1 patients might be exacerbated by transfusions and/or oral iron supplements"

Supports iatrogenic iron as an EXACERBATES influence on the hepatic overload node.

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Biochemical Markers

2

Low plasma ferritin despite iron stores (Present)

Show evidence (1 reference)

PMID:21871825 SUPPORT Human Clinical

"Mutations in the human SLC11A2 gene coding DMT1 lead to microcytic anemia and hepatic iron overload, with unexpectedly low levels of plasma ferritin in the presence of iron stores."

Directly reports the low-ferritin-with-iron-stores signature.

Increased soluble transferrin receptor (Present)

Show evidence (1 reference)

PMID:19786204 SUPPORT Human Clinical

"increased saturation of transferrin (Tf), slightly elevated ferritin, and increased soluble transferrin receptor (sTfR)."

Reports the increased soluble transferrin receptor in affected patients.

🔬

Diagnosis

1

Iron studies with SLC11A2 sequencing

The combination of hypochromic microcytic anemia with high serum iron, increased transferrin saturation, low-to-normal ferritin, raised soluble transferrin receptor, and hepatic iron overload distinguishes AHMIO1 from iron-deficiency anemia; SLC11A2 sequencing confirms the diagnosis and prevents counterproductive iron therapy.

Show evidence (1 reference)

PMID:19786204 SUPPORT Human Clinical

"Serum markers could be particularly useful to establish a correct diagnosis: high serum iron, normal total iron-binding capacity (TIBC), increased saturation of transferrin (Tf), slightly elevated ferritin, and increased soluble transferrin receptor (sTfR)."

Names the serum-marker pattern used to reach the diagnosis.

📊

Prevalence

1

Global published literature

Cases In Literature Ultra Rare

A time-bounded diagnosed-case count from the literature, not a population prevalence estimate. As of 2022 roughly ten patients had been reported worldwide.

Show evidence (2 references)

PMID:35457224 SUPPORT Human Clinical

"Mutations in SLC11A2 cause an ultra-rare hypochromic microcytic anemia with iron overload (AHMIO1), which has been described in eight patients so far."

Direct published statement of the disease rarity and cumulative case count.

PMID:35457224 SUPPORT Human Clinical

"being the ninth and tenth world-wide identified cases"

The two new 2022 cases bring the worldwide total to about ten.

🐁

Animal Models

2

mk mouse (Slc11a2 G185R)

The microcytic anemia (mk) mouse carries a spontaneous G185R DMT1 missense mutation. It reproduces the erythroid iron-utilization defect and the hypochromic microcytic anemia of DMT1 deficiency, but - unlike affected humans - it is iron-deficient rather than hepatic-iron-overloaded, which is the feature that names the human disease.

Species

Mouse

Genotype

Slc11a2 G185R (mk) homozygous

Publication

PMID:15459009

Pathograph links

Impaired Erythroid Transferrin-Cycle Iron Utilization recapitulates fidelity: high The mk mouse reproduces defective erythroid iron utilization and the resulting hypochromic microcytic anemia.

Readouts

Erythroid iron utilization and red-cell indices

Direction: DECREASED

Interpretation: Hypochromic microcytic anemia with defective red-cell-precursor iron use is the model correlate of the erythroid iron-utilization node.

Show evidence (1 reference)

PMID:15459009 SUPPORT Model Organism

"These animals exhibit hypochromic microcytic anemia due to impaired intestinal iron absorption, and defective iron utilization in red cell precursors."

Reports the erythroid iron-utilization defect and anemia in the mk/Belgrade rodent models.

Show evidence (1 reference)

PMID:15459009 SUPPORT Model Organism

"These animals exhibit hypochromic microcytic anemia due to impaired intestinal iron absorption, and defective iron utilization in red cell precursors."

Supports treating the mk mouse as informative for the erythroid iron-utilization node.

Hepatic Iron Overload via DMT1-Independent Uptake fails to recapitulate fidelity: low The rodent DMT1-mutant models are iron-deficient, not iron-overloaded, so they do not spontaneously reproduce the hepatic iron loading that defines the human disease.

Limitations: The paradoxical hepatic overload of the human disease is precisely what the mk mouse does not show, so translational inference about the hepatic arm from this model is unsound - the mismatch modeled in the HUMAN_MODEL_MISMATCH discussion.

Show evidence (1 reference)

PMID:15459009 SUPPORT Model Organism

"unlike the animal models of DMT1 mutation, the patient is iron overloaded"

States outright that the DMT1-mutant animal models are not iron overloaded, unlike the human patient.

Belgrade rat (Slc11a2 G185R)

The Belgrade (b) rat carries the same G185R DMT1 mutation as the mk mouse. Spontaneously it shows severe microcytic anemia and defective erythroid iron use; when exogenously iron-loaded it deposits iron in the liver through a DMT1-independent route, demonstrating the hepatic-uptake pathway central to the human disease.

Species

Rat

Genotype

Slc11a2 G185R (b) homozygous

Publication

PMID:35457224

Pathograph links

Impaired Erythroid Transferrin-Cycle Iron Utilization recapitulates fidelity: high The Belgrade rat reproduces the severe congenital microcytic anemia and defective erythroid iron use of DMT1 deficiency.

Show evidence (1 reference)

PMID:16160008 SUPPORT Model Organism

"Both mk mice and Belgrade rats, which carry an identical DMT1 mutation, exhibit severe microcytic anemia at birth and defective intestinal iron use and erythroid iron use."

Reports severe microcytic anemia and defective erythroid iron use in the Belgrade rat.

Hepatic Iron Overload via DMT1-Independent Uptake partially recapitulates fidelity: moderate Under exogenous iron loading the Belgrade rat deposits iron in the liver despite DMT1 loss, demonstrating the DMT1-independent hepatic uptake route (probably ZIP14) that drives the human hepatic overload.

Limitations: The rat loads hepatic iron only when given iron dextran; it does not develop the spontaneous hepatic overload seen in affected humans, so it models the DMT1-independent uptake route rather than the spontaneous overloaded state.

Show evidence (1 reference)

PMID:35457224 SUPPORT Model Organism

"The injection of iron dextran in the Belgrade rat (DMT1 G185R) improved its anemic state but led to hepatic iron deposition"

Shows DMT1-independent hepatic iron deposition in the iron-loaded Belgrade rat, the model correlate of the hepatic-overload node.

{ }

Source YAML

click to show

name: Microcytic Anemia With Liver Iron Overload
creation_date: "2026-09-02T00:00:00Z"
description: >-
  Microcytic anemia with liver iron overload (AHMIO1) is an ultra-rare autosomal
  recessive disorder caused by biallelic loss-of-function variants in SLC11A2,
  which encodes the divalent metal transporter 1 (DMT1). DMT1 performs two
  distinct iron-handling jobs: apical iron uptake at the duodenal brush border,
  and release of transferrin-cycle iron from recycling endosomes into the
  cytosol of erythroid precursors. Loss of the erythroid function starves
  developing red cells of iron for haemoglobin synthesis, producing a severe
  hypochromic microcytic anemia present from birth. The paradox that defines the
  disease is that this iron-deficient erythropoiesis coexists with systemic and
  hepatic iron overload: liver iron uptake does not depend on DMT1, so in the
  face of high serum iron and transferrin saturation the liver continues to load
  iron through DMT1-independent routes (non-transferrin-bound iron via ZIP14).
  Because standard management of a microcytic anemia (oral iron, transfusion)
  worsens the iron loading, correct early diagnosis is clinically important, and
  recombinant erythropoietin is the reported treatment of choice.
synonyms:
- AHMIO1
- anemia, hypochromic microcytic, with iron overload 1
- hypochromic microcytic anemia with iron overload
- microcytic anaemia and hepatic iron overload
- DMT1 deficiency
- SLC11A2-related microcytic anemia
category: Mendelian
disease_term:
  preferred_term: microcytic anemia with liver iron overload
  term:
    id: MONDO:0008787
    label: microcytic anemia with liver iron overload
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0008787
      label: microcytic anemia with liver iron overload
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
parents:
- hereditary anemia
- disorder of iron metabolism and transport
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Reported patients have been homozygous or compound heterozygous for SLC11A2
    variants, with healthy heterozygous carrier parents.
  evidence:
  - reference: PMID:15459009
    reference_title: Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This homozygous mutation in the ultimate nucleotide of exon 12 codes for a
      conservative E399D amino acid substitution
    explanation: >-
      The first reported patient was homozygous for the causative SLC11A2
      variant, establishing recessive transmission.
  - reference: PMID:16160008
    reference_title: Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report the hematologic phenotype of a child, compound heterozygote for 2
      DMT1 mutations, who was affected by severe anemia since birth and showed
      hepatic iron overload.
    explanation: >-
      Independent patient with biallelic compound heterozygous transmission.
prevalence:
- population: Global published literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A time-bounded diagnosed-case count from the literature, not a population
    prevalence estimate. As of 2022 roughly ten patients had been reported
    worldwide.
  evidence:
  - reference: PMID:35457224
    reference_title: New Cases of Hypochromic Microcytic Anemia Due to Mutations in the SLC11A2 Gene and Functional Characterization of the G75R Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in SLC11A2 cause an ultra-rare hypochromic microcytic anemia with
      iron overload (AHMIO1), which has been described in eight patients so far.
    explanation: >-
      Direct published statement of the disease rarity and cumulative case count.
  - reference: PMID:35457224
    reference_title: New Cases of Hypochromic Microcytic Anemia Due to Mutations in the SLC11A2 Gene and Functional Characterization of the G75R Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      being the ninth and tenth world-wide identified cases
    explanation: >-
      The two new 2022 cases bring the worldwide total to about ten.
pathophysiology:
- name: SLC11A2/DMT1 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic SLC11A2 variants reduce or abolish functional DMT1, the
    proton-coupled divalent metal transporter that carries ferrous iron across
    membranes. Different alleles act by different molecular routes - defective
    protein processing and endoplasmic-reticulum retention (R416C), lysosomal
    mis-accumulation and degradation (G75R), or exon skipping that leaves only a
    small amount of functional transporter (E399D) - but all converge on
    quantitatively reduced DMT1 activity.
  genes:
  - preferred_term: SLC11A2
    term:
      id: hgnc:10908
      label: SLC11A2
  molecular_functions:
  - preferred_term: iron ion transmembrane transporter activity
    modifier: DECREASED
    term:
      id: GO:0005381
      label: iron ion transmembrane transporter activity
  evidence:
  - reference: PMID:15459009
    reference_title: Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report here the first human mutation of DMT1 identified in a female with
      severe hypochromic microcytic anemia and iron overload.
    explanation: >-
      Establishes DMT1/SLC11A2 loss of function as the cause of the human
      disease.
  - reference: PMID:16584902
    reference_title: A novel R416C mutation in human DMT1 (SLC11A2) displays pleiotropic effects on function and causes microcytic anemia and hepatic iron overload.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We propose that DMT1(C1246T) (R416C) represents a complete loss-of-function,
      and that a quantitative reduction in DMT1 expression is the cause of the
      microcytic anemia and iron overload in the patient.
    explanation: >-
      Functional characterisation showing a disease allele is a complete
      loss-of-function producing a quantitative reduction in transporter.
  - reference: PMID:16023393
    reference_title: Functional characterization of the E399D DMT1/NRAMP2/SLC11A2 protein produced by an exon 12 mutation in a patient with microcytic anemia and iron overload.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This indicates that DMT1G1285C is not a complete loss of function but rather
      that a modest amount of active DMT1 is produced in this patient.
    explanation: >-
      Supports the node's E399D claim that the exon-12 allele leaves only a small
      amount of functional transporter rather than abolishing it, from functional
      assays of the mutant expressed in LLC-PK1 cells.
  downstream:
  - target: Impaired Erythroid Transferrin-Cycle Iron Utilization
    description: >-
      DMT1 releases transferrin-cycle iron from recycling endosomes into the
      cytosol of erythroid precursors; its loss blocks this erythroid iron use.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16160008
      reference_title: Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Divalent metal transporter 1 (DMT1) mediates apical iron uptake in duodenal
        enterocytes and iron transfer from the transferrin receptor endosomal cycle
        into the cytosol in erythroid cells.
      explanation: >-
        Names the erythroid transferrin-endosomal-cycle iron transfer that DMT1
        loss disrupts.
  - target: Impaired Duodenal Iron Absorption
    description: >-
      DMT1 mediates apical (brush-border) iron uptake in duodenal enterocytes,
      so its loss impairs dietary iron absorption.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16023393
      reference_title: Functional characterization of the E399D DMT1/NRAMP2/SLC11A2 protein produced by an exon 12 mutation in a patient with microcytic anemia and iron overload.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        DMT1 (Nramp2, Slc11a2) mediates iron uptake at the intestinal brush border
        and across the membrane of acidified endosomes.
      explanation: >-
        Names the brush-border absorptive function that DMT1 loss impairs; a
        general background statement from an in-vitro functional-characterization
        paper.
  - target: Hepatic Iron Overload via DMT1-Independent Uptake
    description: >-
      Liver iron uptake does not require DMT1, so its loss does not protect the
      liver; hepatic iron loading proceeds through other pathways.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16160008
      reference_title: Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The early onset of iron overload indicates that, as in animal models, DMT1
        is dispensable for liver iron uptake, whereas its deficiency in the gut is
        likely bypassed by the up-regulation of other pathways of iron use.
      explanation: >-
        States that liver iron uptake is DMT1-independent, the basis for the
        paradoxical hepatic overload.
- name: Impaired Erythroid Transferrin-Cycle Iron Utilization
  biological_scale: CELLULAR
  description: >-
    In erythroid precursors, iron delivered by transferrin is internalised
    through the transferrin-receptor cycle and must be exported from the
    recycling endosome into the cytosol by DMT1 to reach the mitochondrion for
    haem synthesis. Loss of DMT1 leaves iron trapped in the endosome, starving
    haemoglobin synthesis despite adequate whole-body iron.
  cell_types:
  - preferred_term: erythroblast
    term:
      id: CL:0000765
      label: erythroblast
  biological_processes:
  - preferred_term: iron ion transmembrane transport
    modifier: DECREASED
    term:
      id: GO:0034755
      label: iron ion transmembrane transport
  cellular_components:
  - preferred_term: recycling endosome
    term:
      id: GO:0055037
      label: recycling endosome
  evidence:
  - reference: PMID:35457224
    reference_title: New Cases of Hypochromic Microcytic Anemia Due to Mutations in the SLC11A2 Gene and Functional Characterization of the G75R Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DMT1 has a vital role in iron homeostasis by mediating iron uptake in the
      intestine and kidneys and by recovering iron from recycling endosomes after
      transferrin endocytosis.
    explanation: >-
      Establishes the recycling-endosome iron-recovery step that is lost in
      erythroid precursors.
  downstream:
  - target: Microcytic anemia
    description: >-
      Failure of erythroid iron utilization blocks haemoglobin synthesis,
      producing hypochromic microcytic anemia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15459009
      reference_title: Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The lack of full-length mRNA would predict deficient iron absorption in
        the intestine and deficient iron utilization in erythroid precursors
      explanation: >-
        Names the deficient erythroid iron utilization that produces the anemia;
        the source frames it as a prediction from the loss of full-length mRNA.
  - target: Elevated circulating iron concentration
    description: >-
      Iron delivered to erythroid precursors but not utilized for haemoglobin
      synthesis is left unconsumed, so serum iron rises even as red-cell iron
      falls.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:19786204
      reference_title: "Mutations in the gene encoding DMT1: clinical presentation and treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        high serum iron, normal total iron-binding capacity (TIBC), increased
        saturation of transferrin (Tf), slightly elevated ferritin, and increased
        soluble transferrin receptor (sTfR).
      explanation: >-
        The high serum iron accompanying iron-deficient erythropoiesis is the
        observed correlate of erythroid iron underutilization leaving circulating
        iron unconsumed.
  - target: Elevated transferrin saturation
    description: >-
      With circulating iron rising and iron-binding capacity normal, transferrin
      saturation increases - the iron-overloaded serum profile that separates the
      disorder from iron-deficiency anemia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:19786204
      reference_title: "Mutations in the gene encoding DMT1: clinical presentation and treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        high serum iron, normal total iron-binding capacity (TIBC), increased
        saturation of transferrin (Tf)
      explanation: >-
        Increased transferrin saturation with normal TIBC is the reported serum
        correlate of unconsumed circulating iron in this disorder.
- name: Impaired Duodenal Iron Absorption
  biological_scale: CELLULAR
  description: >-
    DMT1 imports dietary ferrous iron across the apical brush-border membrane of
    duodenal enterocytes. Its loss impairs intestinal iron absorption; in humans,
    however, this is partly bypassed by up-regulation of other absorptive
    pathways, so intestinal loss alone does not produce iron deficiency.
  cell_types:
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  biological_processes:
  - preferred_term: iron ion transmembrane transport
    modifier: DECREASED
    term:
      id: GO:0034755
      label: iron ion transmembrane transport
  cellular_components:
  - preferred_term: brush border membrane
    term:
      id: GO:0031526
      label: brush border membrane
  evidence:
  - reference: PMID:15459009
    reference_title: Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Divalent metal transporter 1 (DMT1) is a transmembrane protein crucial for
      duodenal iron absorption and erythroid iron transport.
    explanation: >-
      Establishes the duodenal iron-absorption function impaired by DMT1 loss.
  notes: >-
    No downstream edge to the anemia is drawn from this node: the cited source
    (PMID:16160008) states the intestinal defect "is likely bypassed by the
    up-regulation of other pathways of iron use", so in humans the duodenal loss
    does not measurably contribute to the phenotype. The compensation is kept as
    node description rather than asserted as a causal contribution its own
    citation denies.
- name: Hepatic Iron Overload via DMT1-Independent Uptake
  biological_scale: TISSUE
  description: >-
    Because hepatocyte iron uptake does not require DMT1, and serum iron and
    transferrin saturation are high, the liver continues to acquire iron through
    DMT1-independent routes - non-transferrin-bound iron entering hepatocytes
    probably via the ZIP14 transporter. Transfusion and oral iron given for the
    anemia further exacerbate this loading.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:35457224
    reference_title: New Cases of Hypochromic Microcytic Anemia Due to Mutations in the SLC11A2 Gene and Functional Characterization of the G75R Mutation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This DMT1-independent iron acquisition, in a high serum iron level condition,
      is performed probably through the ZIP14 transporter
    explanation: >-
      Names the DMT1-independent hepatic uptake route (ZIP14) operating under high
      serum iron. Cited as MODEL_ORGANISM because this sentence describes the
      Belgrade rat.
  downstream:
  - target: Elevated hepatic iron concentration
    description: >-
      Continued DMT1-independent hepatic iron acquisition deposits iron in the
      liver.
    causal_link_type: DIRECT
phenotypes:
- name: Microcytic anemia
  description: >-
    Severe hypochromic microcytic anemia is the presenting feature, present from
    birth, and reflects failed erythroid iron utilization for haemoglobin
    synthesis.
  phenotype_term:
    preferred_term: Hypochromic microcytic anemia
    term:
      id: HP:0004840
      label: Hypochromic microcytic anemia
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:19786204
    reference_title: "Mutations in the gene encoding DMT1: clinical presentation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This recessively inherited condition appears at birth with severe microcytic
      anemia.
    explanation: >-
      Establishes the congenital, severe microcytic anemia as the core phenotype.
- name: Elevated hepatic iron concentration
  description: >-
    Liver iron overload, documented by MRI and/or biopsy, is present in the
    majority of reported patients and is the feature that pairs paradoxically
    with the anemia.
  phenotype_term:
    preferred_term: Liver iron overload
    term:
      id: HP:0012465
      label: Elevated hepatic iron concentration
  evidence:
  - reference: PMID:19786204
    reference_title: "Mutations in the gene encoding DMT1: clinical presentation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover liver iron overload was present and documented in all of the
      affected patients.
    explanation: >-
      Documents hepatic iron overload across the reported patient series.
- name: Elevated circulating iron concentration
  description: >-
    High serum iron accompanies the anemia, distinguishing the disorder from a
    true iron-deficiency anemia despite the shared microcytic blood picture.
  phenotype_term:
    preferred_term: High serum iron
    term:
      id: HP:0003452
      label: Increased circulating iron concentration
  evidence:
  - reference: PMID:19786204
    reference_title: "Mutations in the gene encoding DMT1: clinical presentation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      high serum iron, normal total iron-binding capacity (TIBC), increased
      saturation of transferrin (Tf), slightly elevated ferritin, and increased
      soluble transferrin receptor (sTfR).
    explanation: >-
      Reports the high serum iron that characterises the biochemical profile.
- name: Elevated transferrin saturation
  description: >-
    Transferrin saturation is increased, part of the iron-overloaded serum
    profile that separates this disease from iron-deficiency anemia.
  phenotype_term:
    preferred_term: Increased transferrin saturation
    term:
      id: HP:0012463
      label: Elevated transferrin saturation
  evidence:
  - reference: PMID:19786204
    reference_title: "Mutations in the gene encoding DMT1: clinical presentation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      increased saturation of transferrin (Tf)
    explanation: >-
      Reports the increased transferrin saturation in the biochemical profile.
biochemical:
- name: Low plasma ferritin despite iron stores
  presence: Present
  specificity: Supportive
  biomarker_term:
    preferred_term: Decreased circulating ferritin concentration
    term:
      id: HP:0012343
      label: Decreased circulating ferritin concentration
  notes: >-
    An unexpectedly low plasma ferritin in the presence of demonstrable iron
    stores is a distinctive clue, since ferritin is usually high in iron
    overload.
  evidence:
  - reference: PMID:21871825
    reference_title: A novel N491S mutation in the human SLC11A2 gene impairs protein trafficking and in association with the G212V mutation leads to microcytic anemia and liver iron overload.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in the human SLC11A2 gene coding DMT1 lead to microcytic anemia
      and hepatic iron overload, with unexpectedly low levels of plasma ferritin
      in the presence of iron stores.
    explanation: >-
      Directly reports the low-ferritin-with-iron-stores signature.
- name: Increased soluble transferrin receptor
  presence: Present
  specificity: Supportive
  notes: >-
    Increased soluble transferrin receptor reflects iron-deficient
    erythropoiesis at the cellular level despite systemic iron excess.
  evidence:
  - reference: PMID:19786204
    reference_title: "Mutations in the gene encoding DMT1: clinical presentation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      increased saturation of transferrin (Tf), slightly elevated ferritin, and
      increased soluble transferrin receptor (sTfR).
    explanation: >-
      Reports the increased soluble transferrin receptor in affected patients.
genetic:
- name: SLC11A2 biallelic pathogenic variants
  gene_term:
    preferred_term: SLC11A2
    term:
      id: hgnc:10908
      label: SLC11A2
  association: Causative
  relationship_type: CAUSATIVE
  notes: >-
    Reported causative alleles include the homozygous exon-12 splice/E399D
    variant (first case), the compound heterozygous intron-4 deletion plus R416C,
    the G212V and N491S trafficking-defective variants, and the recurrent G75R
    (a possible founder allele in Ecuadorian patients). Variants act through
    defective processing, ER retention, lysosomal degradation, or aberrant
    splicing, all reducing functional DMT1.
  evidence:
  - reference: PMID:15459009
    reference_title: Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report here the first human mutation of DMT1 identified in a female with
      severe hypochromic microcytic anemia and iron overload.
    explanation: >-
      The first reported causative SLC11A2/DMT1 genotype.
  - reference: PMID:16160008
    reference_title: Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The novel mutations were a 3-bp deletion in intron 4 (c.310-3_5del CTT)
      resulting in a splicing abnormality and a C>T transition at nucleotide
      1246(p. R416C).
    explanation: >-
      An independent biallelic (compound heterozygous) causative genotype.
  - reference: PMID:21871825
    reference_title: A novel N491S mutation in the human SLC11A2 gene impairs protein trafficking and in association with the G212V mutation leads to microcytic anemia and liver iron overload.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the N491S mutation, through its deleterious effect on protein trafficking,
      contributes together with the G212V mutation to the development of anemia and
      hepatic iron overload.
    explanation: >-
      A further biallelic genotype (G212V plus N491S) with a trafficking-based
      mechanism.
diagnosis:
- name: Iron studies with SLC11A2 sequencing
  description: >-
    The combination of hypochromic microcytic anemia with high serum iron,
    increased transferrin saturation, low-to-normal ferritin, raised soluble
    transferrin receptor, and hepatic iron overload distinguishes AHMIO1 from
    iron-deficiency anemia; SLC11A2 sequencing confirms the diagnosis and
    prevents counterproductive iron therapy.
  evidence:
  - reference: PMID:19786204
    reference_title: "Mutations in the gene encoding DMT1: clinical presentation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Serum markers could be particularly useful to establish a correct diagnosis:
      high serum iron, normal total iron-binding capacity (TIBC), increased
      saturation of transferrin (Tf), slightly elevated ferritin, and increased
      soluble transferrin receptor (sTfR).
    explanation: >-
      Names the serum-marker pattern used to reach the diagnosis.
treatments:
- name: Recombinant erythropoietin
  description: >-
    Recombinant erythropoietin is the reported treatment of choice: all described
    patients responded, with improved haemoglobin. Mean corpuscular volume and
    mean corpuscular haemoglobin did not change during treatment, so erythropoietin
    is thought to act by reducing erythroblast apoptosis (relieving ineffective
    erythropoiesis) rather than by improving erythroid iron utilization, and it may
    also help mobilise excess hepatic iron.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: recombinant erythropoietin
      term:
        id: NCIT:C477
        label: Recombinant Erythropoietin
  target_phenotypes:
  - preferred_term: Hypochromic microcytic anemia
    term:
      id: HP:0004840
      label: Hypochromic microcytic anemia
  evidence:
  - reference: PMID:19786204
    reference_title: "Mutations in the gene encoding DMT1: clinical presentation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients appeared to respond to erythropoietin (Epo) administration.
    explanation: >-
      Reports the erythropoietin response across the affected patients.
  - reference: PMID:19786204
    reference_title: "Mutations in the gene encoding DMT1: clinical presentation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      it was concluded that Epo did not improve iron utilization of the erythroblasts
      but likely reduced the degree or intensity of apoptosis, affecting
      erythropoiesis.
    explanation: >-
      States the proposed mechanism of erythropoietin benefit (reduced apoptosis,
      not improved iron use).
- name: Avoidance of iron supplementation and routine transfusion
  description: >-
    Oral iron and transfusion - the default management of a microcytic anemia -
    are counterproductive here because hepatic iron uptake is DMT1-independent, so
    added iron worsens the overload. Recognising the disease early to avoid these
    treatments is a management priority.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Elevated hepatic iron concentration
    term:
      id: HP:0012465
      label: Elevated hepatic iron concentration
  evidence:
  - reference: PMID:35457224
    reference_title: New Cases of Hypochromic Microcytic Anemia Due to Mutations in the SLC11A2 Gene and Functional Characterization of the G75R Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we suggest that liver iron accumulation observed in some AHMIO1 patients might
      be exacerbated by transfusions and/or oral iron supplements, the gold standard
      treatments for general anemic patients.
    explanation: >-
      Directly supports avoiding iron supplementation and transfusion because they
      aggravate the iron overload.
animal_models:
- name: mk mouse (Slc11a2 G185R)
  species: Mouse
  genotype: Slc11a2 G185R (mk) homozygous
  publication: PMID:15459009
  description: >-
    The microcytic anemia (mk) mouse carries a spontaneous G185R DMT1 missense
    mutation. It reproduces the erythroid iron-utilization defect and the
    hypochromic microcytic anemia of DMT1 deficiency, but - unlike affected
    humans - it is iron-deficient rather than hepatic-iron-overloaded, which is
    the feature that names the human disease.
  modeled_mechanisms:
  - target: Impaired Erythroid Transferrin-Cycle Iron Utilization
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The mk mouse reproduces defective erythroid iron utilization and the
      resulting hypochromic microcytic anemia.
    readouts:
    - name: Erythroid iron utilization and red-cell indices
      target: Impaired Erythroid Transferrin-Cycle Iron Utilization
      direction: DECREASED
      interpretation: >-
        Hypochromic microcytic anemia with defective red-cell-precursor iron use
        is the model correlate of the erythroid iron-utilization node.
      evidence:
      - reference: PMID:15459009
        reference_title: Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          These animals exhibit hypochromic microcytic anemia due to impaired
          intestinal iron absorption, and defective iron utilization in red cell
          precursors.
        explanation: >-
          Reports the erythroid iron-utilization defect and anemia in the
          mk/Belgrade rodent models.
    evidence:
    - reference: PMID:15459009
      reference_title: Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These animals exhibit hypochromic microcytic anemia due to impaired
        intestinal iron absorption, and defective iron utilization in red cell
        precursors.
      explanation: >-
        Supports treating the mk mouse as informative for the erythroid
        iron-utilization node.
  - target: Hepatic Iron Overload via DMT1-Independent Uptake
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The rodent DMT1-mutant models are iron-deficient, not iron-overloaded, so
      they do not spontaneously reproduce the hepatic iron loading that defines
      the human disease.
    limitations: >-
      The paradoxical hepatic overload of the human disease is precisely what the
      mk mouse does not show, so translational inference about the hepatic arm
      from this model is unsound - the mismatch modeled in the HUMAN_MODEL_MISMATCH
      discussion.
    evidence:
    - reference: PMID:15459009
      reference_title: Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        unlike the animal models of DMT1 mutation, the patient is iron overloaded
      explanation: >-
        States outright that the DMT1-mutant animal models are not iron
        overloaded, unlike the human patient.
- name: Belgrade rat (Slc11a2 G185R)
  species: Rat
  genotype: Slc11a2 G185R (b) homozygous
  publication: PMID:35457224
  description: >-
    The Belgrade (b) rat carries the same G185R DMT1 mutation as the mk mouse.
    Spontaneously it shows severe microcytic anemia and defective erythroid iron
    use; when exogenously iron-loaded it deposits iron in the liver through a
    DMT1-independent route, demonstrating the hepatic-uptake pathway central to
    the human disease.
  modeled_mechanisms:
  - target: Impaired Erythroid Transferrin-Cycle Iron Utilization
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The Belgrade rat reproduces the severe congenital microcytic anemia and
      defective erythroid iron use of DMT1 deficiency.
    evidence:
    - reference: PMID:16160008
      reference_title: Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2).
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Both mk mice and Belgrade rats, which carry an identical DMT1 mutation,
        exhibit severe microcytic anemia at birth and defective intestinal iron use
        and erythroid iron use.
      explanation: >-
        Reports severe microcytic anemia and defective erythroid iron use in the
        Belgrade rat.
  - target: Hepatic Iron Overload via DMT1-Independent Uptake
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Under exogenous iron loading the Belgrade rat deposits iron in the liver
      despite DMT1 loss, demonstrating the DMT1-independent hepatic uptake route
      (probably ZIP14) that drives the human hepatic overload.
    limitations: >-
      The rat loads hepatic iron only when given iron dextran; it does not develop
      the spontaneous hepatic overload seen in affected humans, so it models the
      DMT1-independent uptake route rather than the spontaneous overloaded state.
    evidence:
    - reference: PMID:35457224
      reference_title: New Cases of Hypochromic Microcytic Anemia Due to Mutations in the SLC11A2 Gene and Functional Characterization of the G75R Mutation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The injection of iron dextran in the Belgrade rat (DMT1 G185R) improved its
        anemic state but led to hepatic iron deposition
      explanation: >-
        Shows DMT1-independent hepatic iron deposition in the iron-loaded Belgrade
        rat, the model correlate of the hepatic-overload node.
environmental:
- name: Iatrogenic iron loading from transfusion and oral iron supplementation
  exposure_term:
    preferred_term: exposure to iron
    term:
      id: ECTO:9000087
      label: exposure to iron
  description: >-
    Transfusion and oral iron - the default management of a microcytic anemia -
    add iron that the DMT1-independent hepatic uptake route deposits in the liver,
    aggravating the overload; this is why early recognition to avoid these
    treatments is a management priority.
  evidence:
  - reference: PMID:35457224
    reference_title: New Cases of Hypochromic Microcytic Anemia Due to Mutations in the SLC11A2 Gene and Functional Characterization of the G75R Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we suggest that liver iron accumulation observed in some AHMIO1 patients might
      be exacerbated by transfusions and/or oral iron supplements, the gold standard
      treatments for general anemic patients.
    explanation: >-
      Names iatrogenic transfusion and oral iron as exacerbators of the hepatic
      iron overload.
  influences_mechanisms:
  - target: Hepatic Iron Overload via DMT1-Independent Uptake
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      Exogenously administered iron feeds the DMT1-independent hepatic uptake
      route, worsening hepatic iron loading.
    evidence:
    - reference: PMID:35457224
      reference_title: New Cases of Hypochromic Microcytic Anemia Due to Mutations in the SLC11A2 Gene and Functional Characterization of the G75R Mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Therefore, we suggest that liver iron accumulation observed in some AHMIO1
        patients might be exacerbated by transfusions and/or oral iron supplements
      explanation: >-
        Supports iatrogenic iron as an EXACERBATES influence on the hepatic
        overload node.
discussions:
- discussion_id: ahmio1_human_model_hepatic_overload_mismatch
  prompt: >-
    Why do humans with biallelic SLC11A2/DMT1 loss develop hepatic iron overload
    when the mk mouse and Belgrade rat carrying the analogous G185R mutation are
    iron-deficient rather than iron-overloaded?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Hepatic Iron Overload via DMT1-Independent Uptake
  - animal_models#Mouse
  rationale: >-
    The erythroid and intestinal iron-transport failure of DMT1 deficiency is
    faithfully reproduced by the rodent models, but the paradoxical hepatic iron
    overload that names the human disease is not: the mk mouse and Belgrade rat
    are iron-deficient. The divergence is mechanistically meaningful because it
    localises the open question to the hepatic arm - whether a species difference
    in DMT1-independent hepatic uptake (for example ZIP14-mediated
    non-transferrin-bound iron entry under high serum iron), in dietary iron
    handling, or in iatrogenic iron exposure explains why humans load hepatic iron
    while the analogous rodents do not.
  proposed_experiments:
  - experiment_id: exp_ahmio1_cross_species_hepatic_iron
    name: Cross-species comparison of DMT1-independent hepatic iron uptake
    description: >-
      Compare hepatic non-transferrin-bound-iron uptake and ZIP14 expression in
      DMT1-mutant mk mice and Belgrade rats against human AHMIO1 liver tissue
      under matched high-serum-iron conditions, to determine whether a species
      difference in the DMT1-independent hepatic route explains the divergent
      iron-overload phenotype.
    experiment_type:
      preferred_term: cross-species model comparison experiment
  - experiment_id: exp_ahmio1_iron_loaded_rodent_hepatic
    name: Controlled iron loading of DMT1-mutant rodents
    description: >-
      Systematically iron-load DMT1-mutant rodents (as with the reported iron
      dextran injection in the Belgrade rat) and quantify hepatic iron deposition
      and its ZIP14 dependence, to test whether the human hepatic overload
      reflects the DMT1-independent route operating under the high serum iron of
      untreated or transfused patients.
    experiment_type:
      preferred_term: model-system iron-loading experiment
  evidence:
  - reference: PMID:15459009
    reference_title: Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      unlike the animal models of DMT1 mutation, the patient is iron overloaded
    explanation: >-
      Directly states the human-versus-model divergence in the iron-overload
      phenotype that this discussion is about.
notes: >-
  Named entity. The disease has the OMIM/Orphanet identity "anemia, hypochromic
  microcytic, with iron overload 1" (AHMIO1, OMIM #206100) and is caused by
  SLC11A2 encoding DMT1 (also called NRAMP2). It is distinct from the other
  congenital microcytic anemias and from the sideroblastic anemias: here the
  lesion is an iron transporter, not a heme-synthesis or iron-sulfur-cluster
  enzyme, and the hallmark is the pairing of iron-starved erythropoiesis with
  systemic and hepatic iron loading.

  The central paradox. Loss of one protein produces both iron deficiency in the
  erythron (blocked release of transferrin-cycle iron in red-cell precursors)
  and iron overload in the body (liver iron uptake is DMT1-independent, so it
  continues in the face of high serum iron). This is why the serum profile
  (high iron, high transferrin saturation, low-to-normal ferritin, high soluble
  transferrin receptor) looks contradictory and is diagnostically useful.

  Phenotype completeness. Two of the reported patients did not have documented
  hepatic iron overload, so "with liver iron overload" is characteristic but not
  universal; no frequency bands are assigned because the literature is a small
  case series.

  GeneReviews baseline. A PubMed search for a GeneReviews chapter on SLC11A2 /
  DMT1 microcytic anemia returned no result; the negative is recorded here so the
  check is visibly done. Phenotype and treatment content is therefore anchored to
  the primary case reports and the Iolascon review.

  No module conformance declared. There is no iron-metabolism or heme-synthesis
  module in kb/modules/ at present; a future iron-transport or
  iron-sulfur-cluster module would be the natural home for this entry alongside
  the sideroblastic anemias.

  Deep-research provenance. No automated deep-research report was generated: the
  deep-research providers were non-functional in the curation environment (no API
  keys). Content was instead built by directly mining the seven cached full
  texts/abstracts for this ultra-rare (~10-patient) disease, including the mk
  mouse / Belgrade rat model divergence, the ZIP14-mediated DMT1-independent
  hepatic uptake route, and the erythropoietin treatment rationale.
references:
- reference: PMID:15459009
  title: Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload.
- reference: PMID:16160008
  title: Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2).
- reference: PMID:16584902
  title: A novel R416C mutation in human DMT1 (SLC11A2) displays pleiotropic effects on function and causes microcytic anemia and hepatic iron overload.
- reference: PMID:16023393
  title: Functional characterization of the E399D DMT1/NRAMP2/SLC11A2 protein produced by an exon 12 mutation in a patient with microcytic anemia and iron overload.
- reference: PMID:21871825
  title: A novel N491S mutation in the human SLC11A2 gene impairs protein trafficking and in association with the G212V mutation leads to microcytic anemia and liver iron overload.
- reference: PMID:19786204
  title: "Mutations in the gene encoding DMT1: clinical presentation and treatment."
- reference: PMID:35457224
  title: New Cases of Hypochromic Microcytic Anemia Due to Mutations in the SLC11A2 Gene and Functional Characterization of the G75R Mutation.
datasets: []

📚

References & Deep Research

References

7

PMID:15459009

Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload.

No top-level findings curated for this source.

PMID:16160008

Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2).

No top-level findings curated for this source.

PMID:16584902

A novel R416C mutation in human DMT1 (SLC11A2) displays pleiotropic effects on function and causes microcytic anemia and hepatic iron overload.

No top-level findings curated for this source.

PMID:16023393

Functional characterization of the E399D DMT1/NRAMP2/SLC11A2 protein produced by an exon 12 mutation in a patient with microcytic anemia and iron overload.

No top-level findings curated for this source.

PMID:21871825

A novel N491S mutation in the human SLC11A2 gene impairs protein trafficking and in association with the G212V mutation leads to microcytic anemia and liver iron overload.

No top-level findings curated for this source.

PMID:19786204

Mutations in the gene encoding DMT1: clinical presentation and treatment.

No top-level findings curated for this source.

PMID:35457224

New Cases of Hypochromic Microcytic Anemia Due to Mutations in the SLC11A2 Gene and Functional Characterization of the G75R Mutation.

No top-level findings curated for this source.

Microcytic Anemia With Liver Iron Overload

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References