Expression Study of Genes Involved in Iron Metabolism in Human Tissues 2001
Mutations of the genes encoding proteins involved in iron uptake, transport, and utilization result in various human disorders or animal models with very different clinical presentations and organ involvement.
However, little is known concerning the expression of iron metabolism genes in various human tissues and their eventual concerted regulation. We therefore examined the expression levels of various genes involved in iron uptake, reduction, and storage, in Fe–S protein biogenesis, in mitochondrial electron transport chain, plus the two SOD genes, in human adult tissues by Northern blot analysis.
We observed that most of these genes were ubiquitously expressed, but that their transcript showed strongly different levels in the various tissues investigated denoting different mechanisms for iron utilization in various organs.
However, surprisingly, no correlation could be made between expression pattern of these genes and the clinical presentation resulting in their mutations.
If a molecule plays an important role in iron homeostasis then it might be predicted that a mutation leading to modification of the function of that molecule would result in a distinctive iron related phenotype. This is indeed the case and the role of almost all of the molecules known to be important in iron transport and its regulation has been confirmed by the analysis of inherited disorders of iron metabolism. Summary of mutations in some molecules and the resulting phenotypes are provided in Table 1.
Consequences of mutations in various iron related genes
Fig 1 Major pathways of iron homeostasis and its regulation Dietary iron in either the inorganic or haem form traverses first the brush border membrane then the basolateral membrane of intestinal enterocytes and binds to plasma transferrin. This diferric transferrin supplies iron to immature erythroid cells for haemoglobin synthesis as well as other body cells for their metabolic needs. At the end of their life senescent red cells are phagocytosed by macrophages and iron released from haem by haem oxygenase 1 is returned to the circulation. Excess iron is stored in the liver and this can also be utilized in times of need. The liver-derived peptide hepcidin acts to repress basolateral iron transport in the gut and iron release from macrophages and other cells. Hepcidin in turn respond to signals mediated by HFE, TfR2 and hemojuvelin.
The panels on the right summarize the consequences of mutations in various iron related genes.
Cp ceruloplasmin; Dcytb duodenal cytochrome b; DMT1 divalent metal transporter 1; 2Tf diferric transferrin; Hb haemoglobin; heph hephaestin; Hjv hemojuvelin; HO1 haem oxygenase 1; TfR1 transferrin receptor 1; TfR2 transferrin receptor 2.
Inherited disorders of iron deficiency
Mutations lead to iron deficency anaemia:
Genetic risk factors
Primary iron overload diseases
Mutations lead to body iron loading:
- HFE
- Transferrin receptor 2 (TfR2)
- Hepcidin
- Hemojuvelin (Hjv)
Genetic risk factors
Increased iron adsorption and disorders of erythropoiesis
Mutations lead to tissue iron loading but plasma hypoferraemia:
- Ferroportin (Ireg1)
- Transferrin (Tf)
- Ceruloplasmin (Cp)
Genetic risk factors
