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Date: Monday, June 3, 1996 FOR IMMEDIATE RELEASE Contact: Bob Kuska, NCI Press Office (301)496-6641
When scientists cloned the gene for Wiskott-Aldrich syndrome two years ago, it marked a turning point in the study of this extremely rare and lethal disease. With the gene, researcherscould track down its protein, known as Wiskott-Aldrich syndrome protein (WASP), and explore how abnormal copies of WASP trigger a complex immunodeficiency syndrome affecting bloodplatelets, white blood cells, and in some cases causing cancer.
But WASP has proved an illusive target. Although scientists have been able to predictand characterize its chemical structure, the function of WASP remains open to speculation. Some researchers have suggested the protein stays sequestered in the nucleus of white blood cells andblood platelets; others say it migrates out into the cytoplasm of these cells, where it mediates the transmission of chemical signals originating from the cell membrane.
Now as another step forward in understanding Wiskott-Aldrich syndrome, researchers atthe National Cancer Institute (NCI) and Italy's University of Brescia report for the first time the expression patterns of WASP in various cell types. The scientists show that WASP is detectable in the cytoplasm, not the nucleus, of blood platelets and immune cells known as lymphocytes and monocytes. The finding appears in the June issue of The Journal of Clinical Investigation. Although the study did not explore the function of WASP in these cells, the data support the ideathat the protein might be involved in a signaling pathway in the cytoplasm of blood platelets and certain immune cells. If confirmed, WASP could open up an exciting new lead in human cell biology because it is chemically dissimilar to any known protein and its action appears to be essential to the well being of blood and immune cells.
The protein could also lead to new avenues for cancer research. Although the symptomsof Wiskott-Aldrich syndrome vary from person to person, researchers have noted a high correlation between autoimmune disease and cancer. In a recent survey of 154 people with thesyndrome, 25 percent of the patients with autoimmune disease also developed cancer, often lymphomas and leukemias. In those without a history of autoimmune disease, the cancer rate dropped to 5 percent. David L. Nelson, M.D., an NCI scientist who has studied the syndrome for 25 years and is one of the authors of today's finding, said the malignancies found in Wiskott-Aldrich syndrome are similar to the non-Hodgkin's lymphoma that affects organ transplant patients and people with AIDS.
"As we discover the precise causes of these malignancies over the next few years, I think that Wiskott-Aldrich syndrome will emerge as an important model for exploring the causes ofnon-Hodgkin's lymphoma in people who are immunosuppressed," said Nelson.
In today's study, the researchers also report an unusual finding on the expression of WASP in laboratory cell lines cultured from four people diagnosed with the syndrome. Although all four patients have mutations in the Wiskott-Aldrich gene and show symptoms of the syndrome, two of them produce normal amounts of regular-sized WASP, while the others have no detectable amounts of the protein in their cells.
Analyzing the locations and types of gene mutations in each patient, Nelson andcolleagues hypothesized that the site of a mutation might correlate not only with the expression patterns of the protein, but with specific aspects of the syndrome. For example, a mutation in one region of the gene might lead to blood platelet abnormalities and a mutation in another region might correspond with immune deficiencies. "We were very surprised to discover thes edifferences in protein expression," he said. "If it is confirmed in more patients, I think the finding will have enormous implications for simplifying the complexities of this syndrome."
As a follow up to this study, Nelson said his laboratory already has begun to investigate whether WASP helps to mediate the transmission of chemical signals within the cell. The resultsof this study have been submitted for publication.
Wiskott-Aldrich syndrome is a recessive, X-linked disorder that affects approximately 500 people in the United States. It is associated with abnormal blood platelets, immunodeficiency, and eczema. The average life span of a person with the syndrome is about 11 years, although some people are now surviving into adulthood. The most common causes of death are bleeding, chronic infections, and cancer.
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