Researchers Say They Have Found Iron Overload Gene
Capping a fervent scientific competition, Bay Area researchers appear to have discovered the faulty gene that causes iron overload disease, a sometimes deadly affliction that often goes unnoticed even though it is among the nation’s most common genetic disorders.
About 1.5 million Americans, primarily whites of Northern European origin, have a pair of the faulty genes--a copy from each parent--according to the federal Centers for Disease Control and Prevention. As a result, they absorb from food three to four times the normal amount of iron until the nutrient reaches toxic levels, leading to diabetes, heart failure, liver cancer or arthritis, among other problems.
Moreover, tens of millions of Americans carry one copy of the gene, which boosts their iron absorption by 50% and slightly increases their risk of problems linked to overloading, said Dr. Victor Herbert, a hematologist at the Bronx Veterans Affairs Medical Center.
An experimental test identifying people with the defective genes would be available to physicians within two years, said Dr. Elliott Sigal, president and CEO of Mercator Genetics, the Menlo Park biotechnology firm that made the discovery.
Such a genetic test would be the first to identify or forecast an affliction that is readily curable and preventable, researchers say. The standard treatment for iron overloading is bloodletting.
“This is an important discovery in an important field,” said Dr. Ernest Beutler, a molecular biologist at the Scripps Research Institute in La Jolla. “It opens the door to much more accurate diagnosis.” His group has worked for several years to find the defective gene, he said.
“I’m quite impressed with the work,” he said of the Mercator team’s research, which appears in the August issue of the journal Nature Genetics.
The competition to unlock this genetic mystery has been intense, involving several academic and commercial groups. Molecular biologist Barry Rothenberg, chief executive officer of the San Diego-based biotechnology firm Billups-Rothenberg, said his group independently discovered the same hemochromatosis gene defect in people but has not published the findings yet.
Because the symptoms of genetic iron overloading, also called hereditary hemochromatosis, mimic those of other, more familiar diseases, the condition is often misdiagnosed. So there is scant awareness of it and little solid information on how many Americans it kills, said Dr. Sharon McDonnell, a CDC nutrition specialist.
An estimated 70% to 80% of the iron in the body is tied up in hemoglobin, the red blood cell molecule that carries oxygen. An additional 5% is associated with myoblobin, the muscle fiber protein, while much of the rest is stored in the liver, spleen and bone marrow. An adult man normally has about 4 grams of iron in his body; an adult woman, 2.5.
Normally, only about 10% of the iron in food is absorbed by the small intestine. And the body holds on to iron fiercely, constantly recycling it and losing substantial amounts only from bleeding.
People with hereditary hemochromatosis can pile up so much of the metal in their body that their skin turns rust orange. If the metal tends to accumulate in the pancreas, insulin-producing cells die and the victim develops what doctors call “bronze diabetes,” from the color of the diseased organ.
Currently, doctors test for iron overloading by measuring the blood levels of the two protein molecules that carry iron: ferritin and transferrin. A liver biopsy, in which tissue is extracted with a syringe, is usually done to diagnose advanced disease.
A drawback of those tests is that they work only after the disease process is underway. In contrast, the gene test is expected to identify the predilection for the disease before the overloading starts, said Mercator’s Dr. Roger Wolff, the lead author of the study, which also involved researchers at Stanford and the St. Louis University School of Medicine.
A human being has 23 pairs of chromosomes--a set from each parent--and the researchers, using recombinant DNA techniques, located the candidate hemochromatosis gene in a stretch of chromosome 6. They don’t know what function the gene normally fulfills, but 83% of the 178 patients with diagnosed iron overloading disease had the same mutation in both pairs of chromosome 6.
McDonnell described hemochromatosis as an “eco-genetic disorder,” meaning that whether a person develops the disease depends not only on genetics but also diet. “If you donate blood often and you’re a vegetarian, it will affect you differently than if you eat a lot of meat and are a heavy drinker,” she said.
