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Genetic Cause of Lymphedema Discovered by University of Pittsburgh Researchers – Reported in Nature Genetics

PITTSBURGH, June 29, 2000 — Clinicians have long puzzled over families whose members invariably develop limbs swollen with lymphatic fluid. Now, University of Pittsburgh investigators and their collaborators from the University of Helsinki have pinpointed genetic errors that account for this disease, hereditary lymphedema.

The mutations, described in the June issue of Nature Genetics, occur in the gene for vascular endothelial growth factor receptor – 3 (VEGFR3). This cell receptor is critical for the growth of lymph vessels that are responsible for draining tissues of extracellular fluid. This new information should enable genetic testing, in addition to providing a therapeutic target for inherited forms of lymphedema and for lymphedema that arises from injury, surgery or infection.

"Our work is the first to identify a genetic mutation responsible for lymphedema," stated David Finegold, M.D., associate professor of human genetics at the University of Pittsburgh’s Graduate School of Public Health (GSPH). "This work provides a foundation for understanding a biological mechanism causal for hereditary lymphedema and crucial for the normal development of lymph vessels."

Lymphedema affects as many as 175 million people worldwide. Hereditary lymphedema arises spontaneously in individuals who have the genetic mutation. Secondary lymphedema may result from infection, injury or common surgical procedures such as those for cancer in which lymph nodes are removed. Lymphedema can lead to infection, pain, severe disability or sometimes cancer. Current treatments involve applying pressure to drain the lymph fluid.

An intricate series of fine tubes and nodes stretching throughout the body, the lymph system performs the mundane but critical task of mopping up excess fluid as well as molecules and cells that stray from nearby blood vessels.

As with other organs, development of the lymph system is tightly regulated. One protein involved in the process is VEGF-C, which binds to its receptor, VEGFR3, on the surface of cells lining lymph vessels. In response, VEGFR3 changes shape and triggers events within a cell that lead to the development of the lymph system. People with hereditary lymphedema produce an abnormal version of VEGFR3 that fails to trip the sequence of events leading to normal development. These investigators also have discovered variations in the VEGFR3 gene that are commonly found in the general population and which may increase the risk of developing secondary lymphedema.

"We know that 25 percent of women with breast cancer who undergo mastectomy and lymph node removal will develop lymphedema in their arm. What this and future research may do is allow us to identify individuals at risk of developing lymphedema before surgery so that problems may be anticipated and addressed before severe lymphedema develops," said Robert Ferrell, Ph.D., professor of human genetics at the GSPH. "The ultimate goal is to develop a rational therapy to prevent lymphedema after surgery or injury."

The University of Pittsburgh scientists suspect that other genes are likely to be involved in lymphedema. Through a recently awarded National Institutes of Health grant, they expect to carry out more studies to clarify their recent findings and discover additional genetic mechanisms.

Established in 1948, the GSPH at the University of Pittsburgh is world-renowned for contributions that have influenced public health practices and medical care for millions of people.

For more information about the GSPH at the University of Pittsburgh, access the school's website at

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