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Unmasking nutrition's role in genes and birth defects

Expectant mothers may someday get a personalized menu of foods to eat during pregnancy to complement their genetic makeup as a result of new research at Washington University School of Medicine in St. Louis. Researchers used transparent fish embryos to develop a way to discover how genes and diet interact to cause birth defects.

"By the time most women know they are pregnant, the development of the fetus' organs is essentially complete," said Bryce Mendelsohn, co-author and an M.D./Ph.D. student in the Medical Scientist Training Program at Washington University School of Medicine. "Since we currently do not understand the interaction between genetics and nutrition, the goal of this research was to understand how the lack of a specific nutrient, in this case copper, interacts with an embryo's genetics during early development."

Mendelsohn is doing the research in the laboratory of Jonathan D. Gitlin, M.D., the Helene B. Roberson Professor of Pediatrics at Washington University School of Medicine, director of genetics and genomic medicine at St. Louis Children's Hospital and scientific director of the Children's Discovery Institute.

Mendelsohn and collaborators Stephen L. Johnson, Ph.D., associate professor of genetics at the School of Medicine, and graduate student Chunyue Yin, working with Lila Solnica-Krezel, associate professor of biology at Vanderbilt University, studied the impact of copper metabolism on the development of zebrafish, a vertebrate that develops similarly to humans. Zebrafish have become staples of genetic research because the transparent embryos grow outside of the mother's body, which allows development to be easily observed. The study's results appear in the August issue of Cell Metabolism.

Using techniques designed to get to the core of how the body processes copper, the researchers identified a gene in zebrafish responsible for copper metabolism, called atp7a. They found that variants of the atp7a gene led to the abnormal metabolism of copper, which resulted in impaired development of the fish's notochord, similar to the spine in humans.

In humans, copper is found in all body tissues and is critical for maintaining stable iron levels, connective tissue formation, nerve cell function in the brain, hormone production and pigmentation. The trace metal is commonly found in shellfish, nuts, chocolate and liver.

"Whether a zebrafish embryo has enough copper to develop normally depends not only on the total amount of copper, but on how well this gene functions," Mendelsohn said.

Menkes disease is an inherited disorder of copper metabolism caused by a mutation in the human version of the ATP7A gene. Children who have Menkes disease have seizures, neuronal degeneration, abnormal bone development and kinky, colorless hair. The disease, although very rare, is untreatable and fatal.

The discovery of a vertebrate model to examine copper metabolism in early development will contribute to the understanding of the role of copper in structural birth defects such as scoliosis, an abnormal curvature of the spine. In addition, the availability of the zebrafish model of Menkes disease permits the development of novel therapeutic approaches in affected patients.

The researchers next plan to adapt these same methods to find other genes that affect the body's use of important nutrients during early development. This could provide insight into how poor nutrition and genetic variation act together to contribute to birth defects. "We already know that nutrition is a critical issue in birth defects and that folic acid is an essential supplement in some women for the prevention of spina bifida in the developing fetus," said Gitlin. "The ultimate goal of this research is to bring the power of genomic medicine to every woman. The knowledge of genetic variations serves as a unique, individual guide for providing the essential nutritional intake that will ensure a normal, healthy infant."

The research is also the first scientific discovery to emerge from the Children's Discovery Institute, a collaboration between St. Louis Children's Hospital and Washington University School of Medicine to fund unique research initiatives in child health.

Beth Miller | EurekAlert!
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