Disorders of iron metabolism.
23 Dec 1999-The New England Journal of Medicine (Massachusetts Medical Society)-Vol. 341, Iss: 26, pp 1986-1995
TL;DR: Iron has the capacity to accept and donate electrons readily, interconverting between ferric (Fe2+) and ferrous (Fe3+) forms, which makes it a useful component of cytochromes, oxygen-binding molecules, and many enzymes.
Abstract: Iron has the capacity to accept and donate electrons readily, interconverting between ferric (Fe2+) and ferrous (Fe3+) forms. This capability makes it a useful component of cytochromes, oxygen-bind...
Citations
More filters
••
TL;DR: These studies in human liver cell cultures, mice, and human volunteers indicate that IL-6 is the necessary and sufficient cytokine for the induction of hepcidin during inflammation and that the IL- 6-hepcid in axis is responsible for the hypoferremia of inflammation.
Abstract: Hypoferremia is a common response to systemic infections or generalized inflammatory disorders. In mouse models, the development of hypoferremia during inflammation requires hepcidin, an iron regulatory peptide hormone produced in the liver, but the inflammatory signals that regulate hepcidin are largely unknown. Our studies in human liver cell cultures, mice, and human volunteers indicate that IL-6 is the necessary and sufficient cytokine for the induction of hepcidin during inflammation and that the IL-6-hepcidin axis is responsible for the hypoferremia of inflammation.
2,300 citations
Cites background from "Disorders of iron metabolism."
...1% of the total body iron content and functions as a transit compartment that turns over every 4 hours (16)....
[...]
...that affects patients with acute and chronic infections, inflammatory disorders, and neoplastic diseases (15, 16)....
[...]
••
TL;DR: The gene responsible for the hypochromic anaemia of the zebrafish mutant weissherbst is identified and Ferroportin1 function may be perturbed in mammalian disorders of iron deficiency or overload.
Abstract: 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, DMT1 (refs 1,2,3). 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.
1,553 citations
••
TL;DR: Human hepcidin, a 25-amino acid peptide made by hepatocytes, may be a new mediator of innate immunity and the long-sought iron-regulatory hormone and its role in iron metabolism could lead to new therapies for hemochromatosis and anemia of inflammation.
1,440 citations
••
TL;DR: The OX26 monoclonal antibody against the rat transferrin receptor offers great promise in the delivery of therapeutic agents across the blood-brain barrier to the brain and serves as a potential alternative to viral vector for gene therapy.
Abstract: The membrane transferrin receptor-mediated endocytosis or internalization of the complex of transferrin bound iron and the transferrin receptor is the major route of cellular iron uptake. This efficient cellular uptake pathway has been exploited for the site-specific delivery not only of anticancer drugs and proteins, but also of therapeutic genes into proliferating malignant cells that overexpress the transferrin receptors. This is achieved either chemically by conjugation of transferrin with therapeutic drugs, proteins, or genetically by infusion of therapeutic peptides or proteins into the structure of transferrin. The resulting conjugates significantly improve the cytotoxicity and selectivity of the drugs. The coupling of DNA to transferrin via a polycation or liposome serves as a potential alternative to viral vector for gene therapy. Moreover, the OX26 monoclonal antibody against the rat transferrin receptor offers great promise in the delivery of therapeutic agents across the blood-brain barrier to the brain.
1,000 citations
••
TL;DR: Hepcidin, ferroportin and their regulators represent potential targets for the diagnosis and treatment of iron disorders and anemias.
995 citations
Cites background from "Disorders of iron metabolism."
...In response to the poor bioavailability of iron in many environments, humans and animals have evolved highly efficient mechanisms for iron conservation [1]....
[...]
References
More filters
••
TL;DR: Using linkage-disequilibrium and full haplotype analysis, this paper identified a 250-kilobase region more than 3 megabases telomeric of the major histocompatibility complex (MHC) that is identical-by-descent in 85% of patient chromosomes.
Abstract: Hereditary haemochromatosis (HH), which affects some 1 in 400 and has an estimated carrier frequency of 1 in 10 individuals of Northern European descent, results in multi-organ dysfunction caused by increased iron deposition, and is treatable if detected early. Using linkage-disequilibrium and full haplotype analysis, we have identified a 250-kilobase region more than 3 megabases telomeric of the major histocompatibility complex (MHC) that is identical-by-descent in 85% of patient chromosomes. Within this region, we have identified a gene related to the MHC class I family, termed HLA-H, containing two missense alterations. One of these is predicted to inactivate this class of proteins and was found homozygous in 83% of 178 patients. A role of this gene in haemochromatosis is supported by the frequency and nature of the major mutation and prior studies implicating MHC class I-like proteins in iron metabolism.
3,477 citations
•
TL;DR: Using linkage–disequilibrium and full haplotype analysis, a region more than 3 megabases telomeric of the major histocompatibility complex (MHC) that is identical–by–descent in 85% of patient chromosomes is identified, containing a gene related to the MHC class I family, termed HLA–H, containing two missense alterations.
3,420 citations
••
TL;DR: A new metal-ion transporter in the rat, DCT1, which has an unusually broad substrate range that includes Fe2+, Zn2+, Mn2+, Co2+, Cd2+, Cu2+, Ni2+ and Pb2+.
Abstract: Metal ions are essential cofactors for a wealth of biological processes, including oxidative phosphorylation, gene regulation and free-radical homeostasis. Failure to maintain appropriate levels of metal ions in humans is a feature of hereditary haemochromatosis, disorders of metal-ion deficiency, and certain neurodegenerative diseases. Despite their pivotal physiological roles, however, there is no molecular information on how metal ions are actively absorbed by mammalian cells. We have now identified a new metal-ion transporter in the rat, DCT1, which has an unusually broad substrate range that includes Fe2+, Zn2+, Mn2+, Co2+, Cd2+, Cu2+, Ni2+ and Pb2+. DCT1 mediates active transport that is proton-coupled and depends on the cell membrane potential. It is a 561-amino-acid protein with 12 putative membrane-spanning domains and is ubiquitously expressed, most notably in the proximal duodenum. DCT1 is upregulated by dietary iron deficiency, and may represent a key mediator of intestinal iron absorption. DCT1 is a member of the 'natural-resistance-associated macrophage protein' (Nramp) family and thus its properties provide insight into how these proteins confer resistance to pathogens.
2,989 citations
••
TL;DR: Iron deficiency and iron deficiency anemia are still relatively common in toddlers, adolescent girls, and women of childbearing age and were more likely in those who are minority, low income, and multiparous.
Abstract: Objective. —To determine the prevalence of iron deficiency and iron deficiency anemia in the US population. Design. —Nationally representative cross-sectional health examination survey that included venous blood measurements of iron status. Main Outcome Measures. —lron deficiency, defined as having an abnormal value for at least 2 of 3 laboratory tests of iron status (erythrocyte protoporphyrin, transferrin saturation, or serum ferritin); and iron deficiency anemia, defined as iron deficiency plus low hemoglobin. Participants. —A total of 24 894 persons aged 1 year and older examined in the third National Health and Nutrition Examination Survey (1988-1994). Results. —Nine percent of toddlers aged 1 to 2 years and 9% to 11% of adolescent girls and women of childbearing age were iron deficient; of these, iron deficiency anemia was found in 3% and 2% to 5%, respectively. These prevalences correspond to approximately 700000 toddlers and 7.8 million women with iron deficiency; of these, approximately 240 000 toddlers and 3.3 million women have iron deficiency anemia. Iron deficiency occurred in no more than 7% of older children or those older than 50 years, and in no more than 1% of teenage boys and young men. Among women of childbearing age, iron deficiency was more likely in those who are minority, low income, and multiparous. Conclusion. —lron deficiency and iron deficiency anemia are still relatively common in toddlers, adolescent girls, and women of childbearing age.
1,200 citations
••
TL;DR: A positional cloning strategy is undertaken to identify the causative mutation in mice with microcytic anaemia, and it is suggested that the phenotype is a consequence of a missense mutation in Nramp2 (ref. 5), a previously identified gene of unknown function.
Abstract: Although disorders of iron metabolism are prevalent, iron transport remains poorly understood. To address this problem, we undertook a positional cloning strategy to identify the causative mutation in mice with microcytic anaemia (mk). Homozygous mk/mk mice have microcytic, hypochromic anaemia due to severe defects in intestinal iron absorption and erythroid iron utilization1–4. We report the identification of a strong candidate gene for mk, and suggest that the phenotype is a consequence of a missense mutation in Nramp2 (ref. 5), a previously identified gene of unknown function. Nramp2 is homologous to Nrampl, a gene active in host defense. If Nramp2 is mk, as the cumulative evidence suggests, our findings have broad implications for the understanding of iron transport and resistance to intracellular pathogens.
1,153 citations