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Hepcidin and iron disorders
other hand highlights that, through Fe/S clusters, iron con- trols its own availability. IRP2 binds IRE at normal tissue oxygen, IRP1 acts in hypoxic tissues, such as the duode- num and kidneys.
Murine models of total and tissue-specific IRP inactiva-
tion are providing further insights into the local function of these proteins. Deletion of both Irps in mice is incom- patible with life; loss of Irp2 results in mild anemia, ery- thropoietic protoporphyria and adult-onset neurodegener- ation in mice33 and in patients,34 likely because of function-
Table 1. Genetic and acquired iron disorders. Genetic iron overload without anemia
HH type 1
HH type 2
HH type 3
HH type 4
gain-of-function FPN mutations Ferroportin disease
loss-of-function FPN mutations
Iron-loading genetic anemias
Thalassemia syndromes α−thalassemia β−thalassemia
Congenital sideroblastic anemia (non-syndromic)*
Congenital sideroblastic anemia (syndromic)* SA and ataxia
SIFD
Congenital dyserythropoietic anemia Type1
Type 2, HEMPAS
Type3 Hypotransferrinemia
DMT1 mutations
Genetic iron deficiency IRIDA
Genetic regional iron-FT accumulation
Hyperferritinemia-cataract syndrome
Ferritinopathy
Acquired iron overload
Chronic blood transfusions
Acquired iron-loading anemias
RS MDS
Acquired absolute iron deficiency
Iron deficiency
Acquired functional iron deficiency
Anemia of inflammation
Inheritance
AR
AR
AR
AD
AD
AR AR
Gene
HFE
HJV
HAMP TFR2
SCL40A1
SCL40A1
HBA HBB
Phenotype
Inappropriate low hepcidin Adult-onset iron overload
Low hepcidin
Juvenile iron overload
Low hepcidin Early-onset iron overload
Hepcidin resistance
Severe iron overload Macrophage iron overload
Microcytic anemia + iron overload
Microcytic anemia Ringed sideroblasts Iron overload
SA and ataxia
SA, immunodeficiency and development delay
Anemia, splenomegaly, jaundice, erythroblasts multinuclearity, iron overload
Microcytic anemia, iron overload Microcytic anemia, iron overload
Iron-deficiency anemia Refractoriness to oral iron
High serum ferritin in the absence of iron overload Congenital cataract due to FT deposition in the lens
Brain iron accumulation Neurodegeneration
+ cardiac iron overload
Iron overload requiring chelation therapy
Macrocytic anemia. Ringed sideroblasts. Iron overload
Low body iron ± microcytic anemia
Low serum iron. Normocytic anemia
Macrophage iron accumulation
X-linked
AR SLC25A38
X-linked AR
AR AR
AR AR AR
AR AD
AD AR
Clonal disorder with somatic mutations
ALAS2 GLRX5
HSPA9
ABCB7 TRNT1
CDAN1 C15orf41 SEC23B KIF23
TF SLC11A1
TMPRSS6
FTL promoter (IRE)
FTL FRDA
SF3B1
HH: hereditary hemochromatosis; AR: autosomal recessive; AD: autosomal dominant; FPN: ferroportin; SA: sideroblastic anemia; *only forms of hematologic interest are shown. SIFD:congenital sideroblastic anemia,B-cell immunodeficiency,periodic fevers,and developmental delay;.HEMPAS:hereditary erythroblastic multinuclearity with positive acid- ified serum lysis test; DMT1: divalent metal transporter 1; IRIDA: iron-refractory, iron-deficiency anemia; FT: ferritin; RS MDS: ringed sideroblast myelodysplastic syndrome.
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