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Genetic Research Boosts Understanding of Iron脙艗s Path through Body, Diseases of Iron Metabolism
BOSTON--March 26, 1999--A team of Harvard Medical School and Howard Hughes Medical Institute researchers have found that the transferrin cycle has a more limited role in iron transport than previously believed. The study, published in the April Nature Genetics, may eventually lead to improved diagnosis and treatment of iron metabolism disorders.
Led by Nancy Andrews, associate investigator of the Howard Hughes Medical Institute at Children脙艗s Hospital, Boston and a Harvard Medical School associate professor of pediatrics, the study is the latest in a recent flurry aimed toward a molecular understanding of how iron travels through the body.
Iron metabolism disorders脙鈥簑hich include iron deficiency and iron overload diseases脙鈥篴fflict more than a billion people worldwide. Hemochromatosis, which is caused by an iron overload, is the most common genetic disorder among whites. Affecting up to 1 in 200 Caucasian Americans, hemochromatosis causes diabetes, impotence, arrhythmia and liver failure if untreated脙鈥篴nd doctors often fail to diagnose it. Moreover, researchers are realizing that iron loading is more common among African Americans than previously thought.
Iron metabolism was intensely studied in the 1950s and 脙艗60s, when the physiology of this essential but potentially toxic metal was a research focus at hematology departments nationwide, Andrews says. The work slowed down because techniques to find key proteins in vivo were unavailable. However, the field picked up again when, in 1996, researchers discovered Hfe, the gene causing hemochromatosis and, in 1997, two groups at Harvard, including Andrews脙艗s lab, discovered that another gene, Nramp2, is responsible for transporting dietary iron into the cells lining the small intestine.
Andrews began her research on iron by analyzing a legacy of the old work: strains of mice dating back to the 1920s and 脙沤30s that had defects so carefully described by hematologists that she could tell they likely had mutations in iron transport genes. This work led her group to identify the intestinal iron transporter.
At the same time, it raised doubts about the current dogma regarding the transferrin cycle, whose discovery was a major advance in the field during the 1980s. A central aspect of iron metabolism, the transferrin cycle begins with the transferrin receptor, a protein found on the surface of many cell types, particularly immature red blood cells. It binds iron attached to its carrier protein, transferrin, and causes receptor-studded vesicles to be pinched off inside the cell. Iron exits these vesicles through the transporter Nramp2 and enters mitochondria, which use it to make heme for hemoglobin and generate energy.
In the current study, Andrews and colleagues at Brigham and Women脙艗s Hospital tested whether this cycle was the major mechanism to get iron into all cells of the body, by creating mutant mice lacking the transferrin receptor.
The results confirmed their hunch that the transferrin cycle instead served the more specialized role of concentrating iron mostly in red blood cells, which need especially large amounts of the metal. Not surprisingly, embryos lacking both copies of the gene died in utero of severe anemia. Up to mid-gestation, they survived by importing iron through some other mechanism, but as they grew larger, that alternative could no longer support the demands of blood formation, Andrews says. Most other organs looked normal.
Curiously, the only exception to this was the nervous system. The scientists detected a wave of cell death in the brains of the mutant embryos at a developmental stage when no brain cells die normally. This could mean that developing neurons need so much energy that only the transferrin cycle can pump in enough iron.
The mice lacking only one copy of the gene had abnormally small red blood cells that contained less hemoglobin than normal脙鈥篴gain suggesting that the transferrin cycle operates at maximal capacity during normal erythropoiesis and that half the normal number of transferrin receptors are insufficient to do the job. Since these mice exhibit a form of anemia, the transferrin receptor gene might be mutated in some anemic people, says Andrews, who, as a pediatric hematologist, sees patients with rare forms of this disease.
Moreover, the mutant mice showed a symptom that provides a clue to another pressing question in the field, namely, which proteins control how much dietary iron the intestine absorbs, Andrews adds. The mutant mice have low levels of total body iron, and this probably relates to the fact that the bone marrow has long been known to send a signal to the intestine, where it somehow increases the level of iron taken up from food. Andrews suspects that part of this mysterious signal may be a fragment of the transferrin receptor that is clipped off the cell surface. Without the transferrin receptor, the intestine in the mutant mice may never 脙聫know脙鈥� about the lack of iron in the body脙艗s cells.
But the transferrin receptor alone does not increase intestinal iron absorption, Andrews says. Along with the transferrin receptor knockout, her team mutated in mice the human hemochromatosis gene Hfe. The HFE protein and the transferrin receptor protein are known to bind tightly to one another, and Andrews hopes that by crossing and analyzing these different mouse strains, she will be able to sort out precisely how that interaction determines iron uptake.
In research soon to be published, Andrews has introduced the human hemochromatosis mutation into the mouse Hfe gene to compare its effect to that of completely disabling the protein. The mice carrying the human mutation showed a mild iron overload phenotype that closely resembles the situation in humans with the disease, taking up about three times the normal amount of dietary iron. Interestingly, the mutation脙鈥簑hich probably arose in a seventh century Celt and has spread to wherever Celtic people have migrated since then脙鈥簃ay have survived because its phenotype of increased iron uptake would have been an advantage in times when iron-rich food was scarce and life expectancy was low.
Current treatment for hemochromatosis is bloodletting. Though cheap and effective, most patients hate having a needle stuck in their arms every month, Andrews says. Ultimately, knowing the molecular biology underlying this and other iron diseases may lead to more modern treatments
This study was funded in part by the NIH. First author Joanne Levy, Ou Jin, and Yuko Fujiwara at Children脙艗s, and Frank Kuo at Brigham and Women脙艗s Hospital collaborated with Andrews on this study.
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