By Dean A. Haycock

Special To BioWorld Today

The only way to lower the amount of iron in the body is to bleed. A disposal system like that probably makes people grateful humans have evolved a highly efficient and tightly regulated system for extracting the metal from food.

When this system is defective, however, iron imbalances produce serious side effects. A defect in the Hfe gene, for example, causes the iron uptake mechanism in the intestine to lose control. The result is a familial form of iron overload called haemochromatosis.

But too little iron is a more common and better known problem. By some estimates, more than 1 billion individuals on the planet do not obtain sufficient quantities of the metal from their diets. Many people are surprised to learn that 10 percent of women in the U.S. may be chronically anemic.

Iron is a crucial component in hemoglobin, the molecule that carries oxygen throughout the body. One of the challenges of treating iron-related conditions is understanding how it enters the body. Understanding the uptake system in the intestine was impossible because no one knew what protein did the job. That has changed with the publication of a paper in today's issue of Nature Genetics titled "Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene."

Senior author of the Nature Genetics paper Nancy Andrews and her colleagues at Harvard University Medical School, Children's Hospital, Howard Hughes Medical Institute and Brigham and Women's Hospital, all in Boston, have identified a protein that appears to play an important role in iron uptake. Andrews is an assistant professor of pediatrics at the Harvard Medical School and assistant investigator at Howard Hughes Medical Institute. Andrews and her colleagues tracked down the crucial mammalian transport protein with the help of anemic mice.

Discoveries May Lead To Major Breakthrough

"I think it is a seminal contribution to the field of iron metabolism. It is the first time that somebody has succeeded in identifying — it is highly likely — one of the membrane transporters of iron. Up until now the mechanism and regulation of the intestinal iron transporter was elusive," said Prem Pomka, professor of physiology and medicine at McGill University, in Montreal.

The transporter was identified in "mk" mice, which suffer from microcytic anemia. Microcytic refers to the small red blood cells found in these mice. This and another feature of the mk mice, hypochromia or lack of color, are both consequences of iron deficiency. But unlike anemia caused by lack of iron in the diet, mk anemia cannot be reversed with iron supplements. The mice cannot absorb iron from their diet.

The Boston researchers first tracked the mk gene to chromosome 15. Their genetic mapping studies led them to a gene called Nramp2. Nramp2 previously had been identified because it was similar to Nramp1 (natural resistance-associated macrophage protein), which is involved in host defense. Nramp2, however, had no previously assigned function.

Andrews and her coworkers found that in anemic mice, the Nramp2 gene has an arginine molecule in the spot where glycine resides in the normal gene. While the function of Nramp2 is not certain, Andrews and her colleagues note its similarity to a yeast gene that transports another metal, manganese. Based on their genetic findings and the homology between the mk gene and the manganese-transporting gene, the researchers propose that Nramp2 codes for the long-sought iron transporter.

This suggestion is strengthened by a report that will appear in Thursday's issue of Nature. Matthias Hediger and colleagues at Brigham and Women's Hospital and Harvard Medical School have discovered an iron transport protein called DCT1 in rat gut. Like Nramp2, DCT1 is a member of the Nramp family. Nramp2/DCT1 appears to be the first mammalian metal transporter to be identified.

In addition to studying anemic mice, Andrews also follows human patients in hematology clinics at Children's Hospital. She would like to know if humans have a defect in the same protein as mk mice.

Similar Human Protein Defect Likely

"We suspect very strongly than an analogous mutation occurs in this protein in humans. While I don't think it is a major cause of anemia, I think it is a significant cause of severe iron deficiency anemia in people," Andrews said.

Andrews and her collaborators are in the process of directly cloning out the genes from her human subject and sequencing their Nramp2 genes to identify mutations.

"We think it is very likely we will [find mutations] because the phenotype has a lot of unique characteristics that really make it different from other iron deficiencies," Andrews said.

This type of anemia, which does not respond to iron treatment, is relatively uncommon, but Andrews predicts it will not be quite as rare as people would have thought a few years ago.

Another population that may benefit from this research are patients who suffer from iron overload, which Andrews describes as a major public health problem. The only treatment for this condition is to have blood taken once or twice every month.

Hereditary haemochromatosis, a form of iron overload, is the most common genetic condition in Caucasians of European descent, according to Andrews. Between 1 in 8 to 1 in 10 carry at least one defective haemochromatosis gene. Approximately 1 in 400 inherit both copies of the gene and develop massive iron overload by middle age. Excess iron can also plague patients who receive frequent blood transfusions.

"I think there is a potential for making some kind of drug that could be taken by mouth and might block this intestinal iron transporter specifically," Andrews said. *