June 2001

From Washington University School of Medicine

Copper is critical in early development

St. Louis, June 5, 2001 ó Researchers have discovered that a protein that escorts copper through cells is essential for the proper formation of organs and tissues. Mice lacking this protein are at high risk for birth defects or infant death.

Copper, a nutrient that people take in every day, is essential for processing oxygen. Because it also can do a lot of damage, cells must handle it with kid gloves. The copper-transporting protein, called Atox1, escorts the nutrient to its proper place within cells, according to a study in the June 5 issue of Proceedings of the National Academy of Sciences.

"But to our surprise, we found that Atox1 is critical not only for copper delivery but also for the proper development of organs and tissues," said Jonathan D. Gitlin, M.D. "That has never been shown previously."

Gitlin, the Helene B. Roberson Professor of Pediatrics at Washington University School of Medicine in St. Louis, led the study. He also is a professor of pathology and immunology at the school and a staff physician at St. Louis Childrenís Hospital. The paperís first author was Iqbal Hamza, Ph.D., postdoctoral fellow in pediatrics.

Hamza and Gitlin worked with collaborators in Germany to genetically alter mice. The animalsí offspring were unable to make functional Atox1 protein. Nearly half died before weaning, and the survivors grew only slowly, had low body temperature and were abnormally pigmented. These symptoms develop when mice lack copper.

Then came an unexpected observation. The mice that lived were fertile, producing offspring that also were deficient in Atox1. The babies were extremely short of copper, and many of them had birth defects. The researchers couldnít have made that observation by giving normal mice a low-copper diet because the mothers would have died of copper deficiency. By using Atox1-deficient mice, they could allow the mothers to survive on a normal diet yet still deprive the fetus of this essential nutrient.

Copper from food eventually enters cells. But moving it around inside cells is no simple task because it can be very toxic. Free copper attacks cell membranes, DNA and other cellular components.

"Like a giant station with many trains running in and out, the cell has to know exactly how to get copper to the right spot," Gitlin said. "It canít have it running all over the station. The metal has to go directly to its platform and get on the right train. How does that happen? We now know that Atox1 performs a critical function in delivering copper to the right place."

Several years ago, the Washington University researchers and others isolated and characterized two human genes that code for intracellular copper-transporting proteins. Defects in these genes result in copper-related diseases. In Wilson disease, copper excretion is disrupted, and patients can die from accumulation of copper in the liver or brain. In Menkes disease, patients suffer from copper deficiency and often die in childhood.

These experiments led to the discovery of a whole class of proteins termed copper chaperones. The current study is the first to identify Atox1 as a copper chaperone in cells of mammals.

"Just like chaperones at a prom, these proteins escort copper within the cell. By getting it to the right place, they make sure nothing bad happens on the way," said Gitlin. "They donít go on dates themselves, however. Once they deliver the copper, they turn around, find more copper and go back. Because the cell would sequester free copper, the chaperone says, ĎCome with me, Iíll protect you,í though they also are protecting the cell."

Related research by University of Michigan investigators identified Ctr1, a protein that helps copper enter cells. That study also is reported in the June 5 issue of Proceedings of the National Academy of Sciences.

Additional research by Gitlinís team will focus on why Atox1 is essential to copper metabolism and exactly how it works. The current findings could lead to insights on Wilson disease, which results from just one defective gene but produces symptoms ranging from schizophrenia to liver disease. "One could imagine that variations in Atox1 could account for that," Gitlin said.

Hamza I, Faisst A, Prohaska J, Chen J, Gruss P, Gitlin JD. The metallochaperone Atox1 plays a critical role in perinatal copper homeostasis. Proceedings of the National Academy of Sciences, 98:12, 6848-6852, June 5, 2001.

Funding from the National Institutes of Health supported this research.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.












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