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INTRODUCTION

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Metals are indispensable elements of cell biology. They function as cofactors in many specific proteins and are involved in all major metabolic pathways. Their metabolism and implications in inborn errors of metabolism are still not fully known, but the number of inherited metabolic disorders involving the absorption, transport, or metabolism of metals is rapidly growing. Clinical presentations are very diverse and can involve all organs and systems, including the liver and the central nervous system. Deficiency in metals results in metabolic abnormalities due mostly to loss of function of metal-dependent proteins. On the other hand, excess of metals can result in the unregulated oxidation of proteins, lipids, and other cellular components, causing subsequent tissue injury. Some inherited metal disorders are treatable by chelating drugs or by daily supplementation of the missing metal at pharmacologic doses. Advances in viral gene therapy augur well for improved management of certain disorders of metal metabolism.

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IRON METABOLISM AND ASSOCIATED PEDIATRIC GENETIC DISEASES

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Iron is an important cofactor for heme and for hundreds of mammalian proteins that use iron and iron sulfur clusters as cofactors. Accordingly, iron is an indispensable nutrient, and iron deficiency is one of the most common diseases in the world. In most cases, iron deficiency can be treated with oral iron supplementation. However, there are numerous iron deficiency and iron overload diseases that are caused by genetic defects in proteins involved in regulation of normal systemic iron homeostasis and normal iron cofactor assembly. The latter are less amenable to simple remedies.

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To understand genetic syndromes of iron deficiency and overload, it is important to review how iron is absorbed from the diet, how it is transported through the body, and how it is distributed to various tissues to ensure that cells acquire sufficient iron, while not incurring damage from excess iron deposition, which results in generation of harmful free radicals.

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Iron is taken up from the duodenal lumen by the iron transporter DMT1, which is aided by DCYTB, a reductase that reduces ferric (3+) iron to ferrous (2+) iron, the substrate for transport by DMT1. Iron transits across the polarized basolateral membrane of mucosal cells, where ferroportin, the sole known iron exporter, exports ferrous iron to the circulation, aided by ferroxidase activity provided by membrane-bound hephaestin or circulating ceruloplasmin to generate ferric iron. Transferrin binds ferric iron and transports iron to tissues throughout the body. Cells that need iron express transferrin receptors (TFRC) on their plasma membrane. Upon binding ferric transferrin (TF), the TF-TFRC complex undergoes endosomal internalization and acidification. Iron is released from TF, oxidized by STEAP3, and exported into the cytosol by DMT1. In the cytosol, iron can be incorporated into numerous iron proteins, transported into mitochondria by mitoferrin (MFRN), or sequestered by the multimeric iron storage protein, ferritin.

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The interaction of 2 proteins, hepcidin, a soluble peptide hormone synthesized by hepatocytes, and ferroportin, a ...

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