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Iron homeostasis: insights from genetics and animal models


Disorders that perturb iron balance are among the most prevalent human diseases, but until recently iron transport remained poorly understood. Over the past five years, genetic studies of patients with inherited iron homeostasis disorders and the analysis of mutant mice, rats and zebrafish have helped to identify several important iron-transport proteins. With information being mined from the genomes of four species, the study of iron metabolism has benefited enormously from positional-cloning efforts. Complementing the genomic strategy, targeted mutagenesis in mice has produced new models of human iron diseases. The animal models described in this review offer valuable tools for investigating iron homeostasis in vivo.

Key Points

  • Iron balance must be strictly maintained to ensure that adequate amounts of iron are available for vital functions and to avoid the toxicity that results from iron excess. Disorders of iron deficiency and iron overload develop when iron balance is disrupted.

  • Iron is absorbed by enterocytes in the proximal intestine; it is stored in hepatocytes, used primarily by erythroid cells, and is recycled by specialized macrophages. There are similarities in the iron-transport strategies used by these different cell types, but tissue-specific differences also exist.

  • Two iron transporters, DMT1 (an importer) and ferroportin1 (an exporter — also known as Ireg1 or MTP1), have been identified by positional cloning.

  • Targeted mutagenesis has produced new mouse models of human iron disorders, including models for hereditary haemochromatosis and aceruloplasminaemia.

  • Despite recent advances in our understanding of iron absorption and iron recycling, many mechanistic details remain to be understood.

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I am grateful to all of the members of my laboratory for sharing their insights into iron metabolism. I appreciate help from Bernard Mathey-Prevot, Renee Ned, Carolyn Pettibone and Mark Fleming in providing criticism on an earlier version of the manuscript. Our studies are supported by the National Institutes of Health. I am an Associate Investigator of the Howard Hughes Medical Institute.

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Table: Informative mutations in important iron-metabolism genes (PDF 19 kb)

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Haem proteins contain an iron complex of porphyrin, usually protoporphyrin IX, and function as catalysts in many biological processes.


Oxidation and reduction activity, involving movement of electrons between different chemical entities.


Haemoproteins that take advantage of valence changes in haem iron to facilitate electron or hydrogen transport.


The production of red blood cells. Erythropoiesis takes place in the bone marrow (humans and mice) and spleen (mice only).


Pica is the compulsive consumption of non-nutritive substances including paint chips, salt, ice and clay.


Anaemia characterized by the presence of stainable iron granules in the cytoplasm of erythroid precursors (erythroblasts).


Absence of serum ceruloplasmin. An autosomal, recessive disorder, leading to neurodegenerative disease, liver iron overload and diabetes, caused by mutations in the ceruloplasmin gene.


An abundant plasma glycoprotein that binds iron with high affinity.


Part of the placenta; the syncytial outer layer of the trophoblast, through which the embryo receives nutrients from the mother.


Absorptive cells lining the intestine.


The parenchymal cells of the liver.


Transferrin loaded with iron.


Transferrin that does not contain bound iron.


When red blood cells are smaller than normal, typically because of defects in haemoglobin production.


When red blood cells are poorly haemoglobinized, typically because of defects in haemoglobin production.


Absence of serum transferrin. An autosomal recessive disorder, associated with severe microcytic, hypochromic anaemia and tissue iron overload. Also called hypotransferrinaemia.


The youngest red blood cells normally found in the circulation, freshly released from the bone marrow (or other site of erythropoiesis).


Iron from sources other than haem proteins.


A general term for iron overload.


Deliberate removal of venous blood from a patient.


Swelling caused by the accumulation of fluid in tissues and the body cavity, which often occurs as a result of severe anaemia.

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Figure 1: Distribution of iron within the body.
Figure 2: The transferrin cycle.
Figure 3: Cellular iron transport.