News Release

Search For Iron Transport Mechanism Leads To "Hephaestus," God Of Metal Working,Who Insight Into Iron-Deficiency Anemia

Peer-Reviewed Publication

University of California - San Francisco

Hephaestus, the Greek god of metal-working, wove a net of iron, and ensnared the illicit lovers Ares and Aphrodite making love. Now, centuries later, a newly discovered protein that bears his name is playing an equally revelatory role, exposing an intimate relationship between copper and iron metabolism, and offering researchers an important insight into a cause of iron-deficiency anemia.

The discovery of the Hephaestin gene -- and the protein it encodes -- was made by a team led by researchers at UC San Francisco, in a laboratory high on the hill of San Francisco's Mt. Parnassus.

It is reported in the February issue of Nature Genetics.

The researchers discovered the Hephaestus gene in mice with iron deficiency anemia, and determined that the protein facilitates transport of iron from the intestines into the body's circulatory system. When the gene is mutated, as it is in the mice, iron cannot be transported to the blood, and iron-deficiency anemia occurs.

A like gene exists in humans, thereby offering insight into a condition that affects as much as 25 percent of the world's population.

More broadly, the discovery of Hephaestus offers insight into the overall pathway of iron transport, which follows an intricate three-step path in the body, moving from the intestines through to the circulatory system. A greater understanding of the pathway could shed light on the numerous clinical problems that can develop as a result of iron overload, as well as iron deficiency. Also, the discovery could solve a conundrum that has long puzzled researchers: why supplements of copper, as well as iron, are required to reverse iron-deficiency anemia.

The hephaestin gene, the researchers discovered, produces a copper-bound protein with enzymatic activity that is able to change the valence of iron from its armored state in what is called "iron 2" to its bioavailable state of "iron 3" thereby making available to the body a metal that the ancient Greeks so valued that they enshrined it in deity.

"We've identified one of the key components of the whole iron uptake system," said the lead author of the study, Christopher Vulpe, MD, PhD, who led the study as a postdoctoral fellow in the laboratory of Jane Gitschier, PhD, a professor of medicine and pediatrics at UCSF, a Howard Hughes Medical Institute Investigator and a senior author of the study.

The reason the investigators pursued the question of iron transport is because iron is essential to the life of all living species. It is a constituent of hemoglobin, the protein that carries oxygen to every tissue in the body, and is so valued that the body harbors what it receives, having no physiologic mechanism for excreting the element except through the blood loss. Still, organisms must utilize elaborate molecular mechanisms for the extraction, mobilization and utilization of the metal, which can only be obtained through diet or supplements.

While many cases of iron-deficiency anemia occur as a result of inadequate diet or blood loss, genetic defects in mechanisms involved in iron transport at various stages in the pathway may contribute to susceptibility to anemia, said Vulpe.

"More work needs to be done to determine if and how often genetic defects in iron transport occur in humans," said Gitschier.

Identifying the gene in the anemic mouse model -- the original goal of the study -- was an achievement in itself, and was accomplished through genetic mapping. The researchers were able to pare down their search to a small region on the X chromosome and identified a genetic sequence that became their candidate gene.

But rather than just determining that the identified gene was associated with a specific disorder -- as has happened with such genetic disorders as Huntington's disease, for which there is still limited understanding of how the gene actually acts or, when mutated, wreaks its havoc -- in this study the researchers were actually able to identify the gene's likely role.

They did so by surveying a database of genes in metal metabolism and determining that their gene was extremely similar genetically to another gene, ceruloplasmin, what Vulpe called a "sky blue protein of the blood," already known to be intimately involved in some steps of iron transport--and to contain copper. (Congenital deficiency of ceruloplasmin in mice and humans leads to iron metabolism defects, including iron accumulation in multiple visceral tissues such as the liver and pancreas, as well as the basal ganglia of the brain and the retina of the eye.)

"What's neat about our finding is that we discovered our protein is a homologue of ceruloplasmin and that gives us a clue about what our protein does," said Vulpe. "We knew our gene was important, given the iron deficiency anemia the mutation caused, but determining the similarity to ceruloplasmin gives us a clue that this protein is involved in iron transport, and it gives us a direction for future study."

Researchers have known since 1928 that the only way to successfully treat anemia in iron deficient rats, swine and people is to supplement their diets not only with iron but also with copper.

Without copper, dietary iron enters the intestinal epithelium normally, but cannot exit into the circulation and eventually is lost during the normal turnover of the epithelium. However, the mechanism by which copper plays a role in intestinal iron export has remained obscure. Moreover, some tissues involved in iron transport, including the intestine, do not express ceruloplasmin, thereby leaving open the question of what mechanism contributes to blocked transport of iron from the intestine to the gut.

"We've discovered a homologue to ceruloplasmin that is located specifically in the intestines," said Vulpe, "Hephaestin probably needs copper just like ceruloplasmin to do its job of iron export."

This is fitting, he explained, taking the opportunity to invoke Ares and Aphrodite. Copper in Greek mythology, he said, is linked to Aphrodite (goddess of love and desire) because she arose from the island of Cyprus, the ancient source of the metal copper. And Ares, god of war was linked to iron, perhaps, suggested Vulpe, because of its use in weapons of war.

"So Hephaestus caught the two, copper and iron, Aphrodite and Ares, shall we say, in a compromising position."

Once again, Hephaestus appears to have revealed copper and iron's intimacy. Co-authors of the study were: Yien-Ming Kuo, PhD and Natasha Libina, BS in Jane Gitschier's laboratory at UC San Francisco in the Howard Hughes Medical Institute; Candice Askwith, PhD, of the Department of Pathology at University of Utah School of Medicine; and Therese L. Murphy, BS Lex Cowley, BS and Greg Anderson, PhD at Queensland Institute of Medical Research, Brisbane, Queensland, Australia.

Christopher Vulpe, MD, PhD, is now an assistant professor in the Department of Nutritional Sciences at UC Berkeley.

The study was funded by grants from: Howard Hughes Medical Institute, NIH, National Health and Medical Research Council of Australia.

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For further information on the Greek gods' affair and Hephaestus, refer to: http://www.perseus.tufts.edu/



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