Hereditary lymphedema genetic mutations found

November 07, 2000

ANN ARBOR---University of Michigan scientists have identified genetic mutations that cause a serious medical condition called hereditary lymphedema-distichiasis or LD. Discovering the gene is the first step toward a future diagnostic test for LD and increased scientific understanding of the gene's impact on early development of the heart and lymphatic system.

People with the mutated gene often develop severe lymphedema, or fluid retention in their arms and legs. They also have double rows of eyelashes, a condition called distichiasis. Some members of LD families have other complications---including heart defects, spinal abnormalities and cleft palate.

U-M scientists and collaborators from the University of Arizona discovered that the mutations responsible for LD are located in the FOXC2 gene on chromosome 16. FOXC2 is one of a large group of related transcription factors in what scientists call the forkhead/winged helix family. Like all transcription factors, forkhead genes serve as master control switches that regulate the activity of other genes.

An article describing the FOXC2 mutations will be published in the December 2000 issue of the American Journal of Human Genetics, which is available now on the journal's Web site at (Access the "AJHG Electronic Edition" and click on "Latest articles.")

"Forkhead genes are important, because they play a major role in regulating embryonic development in all animal species," says Thomas W. Glover, Ph.D., a professor of human genetics, pediatrics and communicable diseases in the U-M Medical School, who directed the study. "At least 17 forkhead genes have been identified in humans and 80 in other species, but we know little about how they affect human development and genetic disease."

Because the physical effects of LD are variable and often don't appear until adolescence, Glover says scientists don't know how common the syndrome is. "While LD is a relatively rare genetic disorder, it is probably more common than we think," he says. "Since lymphedema is usually a side-effect of surgery, injury or infection, many physicians don't realize it also can be a genetic disorder. We need greater awareness of LD and other forms of congenital lymphedema, so patients can be diagnosed accurately and treated effectively. In addition, what we learn from this genetic disorder may apply to other more common forms of lymphedema, as well."

In two families in the study, children received an inactive form of the FOXC2 gene from one parent. A child born with lymphedema in a third family had a different type of mutation called a chromosomal translocation, in which a chromosome break shut down the FOXC2 gene. The discovery of the patient with a translocation mutation---which was made by Robert Erickson, M.D., a University of Arizona scientist---was a key to finding the location of the gene, according to Glover.

To scientists, the study is significant, because it is the first discovery of a FOXC2 mutation in humans and only the second known example of a forkhead gene mutation in humans. It also provides important clues to the molecular events involved in development of the heart and lymphatic system---about which little is known.

"FOXC2 is a pleiotrophic developmental gene," Glover says. "This means that a mutation in a single gene produces multiple effects. Studying the effects of FOXC2 mutations in LD families will help us understand why LD shows variable expression from individual to individual. Some children who inherit the mutated gene develop lymphedema only, while others also show severe heart defects and cleft palate."

In future research, Glover and his research associates plan to study laboratory mice in which the FOXC2 gene has been removed---both as a model for lymphedema and to identify other genes regulated by FOXC2 during embryonic development. Glover also hopes to find more families with hereditary lymphedema who are willing to participate in future studies.

"Our immediate goal is to apply a molecular diagnostic test for LD to get a more accurate definition of the syndrome and its frequency," Glover says. "We also hope to learn more about the mechanisms of primary lymphedema and the role of FOXC2 and other forkhead genes in human development and genetic disease."
Funding for the study was provided by the U-M Medical School and the National Institutes of Health. Lymphedema-distichiasis was first identified as a hereditary syndrome in 1954 by James V. Neel, M.D., former U-M professor emeritus of human genetics; Harold Falls, U-M professor emeritus of ophthalmology; and William J. Schull, professor emeritus of human genetics at the University of Texas-Houston.

Jianming Fang, Ph.D., a U-M postdoctoral fellow, is first author on the study. Other U-M collaborators include postdoctoral fellows Susan L. Dagenais, Ph.D., and Martin F. Arlt, Ph.D.; graduate student Michael W. Glynn; Jerome L. Gorski, M.D., U-M professor of pediatrics and communicable diseases and associate professor of human genetics; Robert P. Erickson, M.D., professor of pediatrics at the University of Arizona; and Laurie H. Seaver, M.D., of the J.C. Self Research Institute of Human Genetics in Greenwood, S.C.

NOTE: If you believe LD runs in your family and are interested in participating in future research studies, call the University of Michigan Health System TeleCare line at 1-800-742-2300, category #6245.

University of Michigan

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