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      Iron homeostasis: insights from genetics and animal models

       
      Nature Reviews Genetics
      Springer Science and Business Media LLC

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          Abstract

          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.

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          Most cited references72

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          Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter.

          Defects in iron absorption and utilization lead to iron deficiency and overload disorders. Adult mammals absorb iron through the duodenum, whereas embryos obtain iron through placental transport. Iron uptake from the intestinal lumen through the apical surface of polarized duodenal enterocytes is mediated by the divalent metal transporter, DMTi. A second transporter has been postulated to export iron across the basolateral surface to the circulation. Here we have used positional cloning to identify the gene responsible for the hypochromic anaemia of the zebrafish mutant weissherbst. The gene, ferroportin1, encodes a multiple-transmembrane domain protein, expressed in the yolk sac, that is a candidate for the elusive iron exporter. Zebrafish ferroportin1 is required for the transport of iron from maternally derived yolk stores to the circulation and functions as an iron exporter when expressed in Xenopus oocytes. Human Ferroportin1 is found at the basal surface of placental syncytiotrophoblasts, suggesting that it also transports iron from mother to embryo. Mammalian Ferroportin1 is expressed at the basolateral surface of duodenal enterocytes and could export cellular iron into the circulation. We propose that Ferroportin1 function may be perturbed in mammalian disorders of iron deficiency or overload.
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            The identification of genes with unique and essential functions in the development of the zebrafish, Danio rerio.

            In a large-scale screen, we isolated mutants displaying a specific visible phenotype in embryos or early larvae of the zebrafish, Danio rerio. Males were mutagenized with ethylnitrosourea (ENU) and F2 families of single pair matings between sibling F1 fish, heterozygous for a mutagenized genome, were raised. Egg lays were obtained from several crosses between F2 siblings, resulting in scoring of 3857 mutagenized genomes. F3 progeny were scored at the second, third and sixth day of development, using a stereomicroscope. In a subsequent screen, fixed embryos were analyzed for correct retinotectal projection. A total of 4264 mutants were identified. Two thirds of the mutants displaying rather general abnormalities were eventually discarded. We kept and characterized 1163 mutants. In complementation crosses performed between mutants with similar phenotypes, 894 mutants have been assigned to 372 genes. The average allele frequency is 2.4. We identified genes involved in early development, notochord, brain, spinal cord, somites, muscles, heart, circulation, blood, skin, fin, eye, otic vesicle, jaw and branchial arches, pigment pattern, pigment formation, gut, liver, motility and touch response. Our collection contains alleles of almost all previously described zebrafish mutants. From the allele frequencies and other considerations we estimate that the 372 genes defined by the mutants probably represent more than half of all genes that could have been discovered using the criteria of our screen. Here we give an overview of the spectrum of mutant phenotypes obtained, and discuss the limits and the potentials of a genetic saturation screen in the zebrafish.
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              A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation.

              Iron absorption by the duodenal mucosa is initiated by uptake of ferrous Fe(II) iron across the brush border membrane and culminates in transfer of the metal across the basolateral membrane to the portal vein circulation by an unknown mechanism. We describe here the isolation and characterization of a novel cDNA (Ireg1) encoding a duodenal protein that is localized to the basolateral membrane of polarized epithelial cells. Ireg1 mRNA and protein expression are increased under conditions of increased iron absorption, and the 5' UTR of the Ireg1 mRNA contains a functional iron-responsive element (IRE). IREG1 stimulates iron efflux following expression in Xenopus oocytes. We conclude that IREG1 represents the long-sought duodenal iron export protein and is upregulated in the iron overload disease, hereditary hemochromatosis.
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                Author and article information

                Journal
                Nature Reviews Genetics
                Nat Rev Genet
                Springer Science and Business Media LLC
                1471-0056
                1471-0064
                December 2000
                December 2000
                : 1
                : 3
                : 208-217
                Article
                10.1038/35042073
                11252750
                df3542de-da2f-4041-b01b-c438064437e1
                © 2000

                http://www.springer.com/tdm

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