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Spotlight on Research for 1999
February 1999 (historical)
NIAMS Reasearchers, Partners Discover Gene Mutations
By Kelli Carrington
NIAMS researchers and their collaborators have discovered genetic mutations on chromosome 12 underlying a newly recognized group of inherited inflammatory disorders that includes familial Hibernian fever (FHF). The disorders, collectively known as TRAPS (TNF Receptor-Associated Periodic Syndrome), are characterized by long, dramatic, episodes of high fever, severe pain in the abdomen, chest, or joints; skin rash; and inflammation in or around the eyes. Some patients also develop amyloidosis, a potentially fatal disease in which a blood protein is deposited in vital organs.
The mutations, reported in the April 2 issue of Cell, involve a cell surface receptor for the inflammatory protein tumor necrosis factor (TNF). Patients from seven different families with TRAPS symptoms exhibited the mutations. Normally, the TNF receptor plays a role in the body's defenses against infectious and foreign agents. The receptor mutations are thought to predispose individuals to severe inflammation triggered by emotional stress, minor trauma or--in some cases--no apparent reason.
"These results are very important in helping us further understand the role of the TNF pathway in disease, and may lead to additional treatments, targeted at the cellular level, for many immune-related and inflammatory disorders," said Stephen I. Katz, M.D., Ph.D., director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) in Bethesda, Md. "This discovery marks the first time that TNF receptor mutations have been tied to an inherited disease."
The report's senior author, NIAMS' Daniel Kastner, M.D., had previously led an international consortium in cloning the gene for familial Mediterranean fever (FMF), another hereditary disorder of fever and inflammation common among people of Jewish, Arab, Armenian and Turkish ancestry. After the FMF gene was identified, it became clear that some families with the characteristic periodic fevers did not have FMF mutations. Several of these families also showed a dominant mode of inheritance (FMF is recessive), and were not of Mediterranean ancestry. The symptoms most often reported included fever lasting a week or more; red, swollen eyes; migratory skin rashes; muscle tenderness; joint pain; and sometimes abdominal or chest pain. An unusually high incidence of inguinal hernia in affected men was also noted. Some patients also developed amyloidosis.
This condition had been originally described in a large Irish family in the mid-1980s, and was called familial Hibernian fever to contrast it from FMF. The condition has now been described in several ethnic groups. Initially, it was not clear whether all of these families had mutations in the same gene or in several related genes.
A key advance came about a year ago, when two research teams independently identified a region of chromosome 12 associated with FHF susceptibility. One team was headed by Michael McDermott, M.D., of the Royal London School of Medicine, formerly a postdoctoral fellow in Kastner's lab. The second team is in Adelaide, Australia. Subsequently, a third team of researchers in Helsinki, Finland, extended these results to a large Finnish family. These teams, and scientists from Nottingham, England, and Cork, Ireland, then collaborated to determine which particular gene on chromosome 12 caused periodic fevers.
The target region contained as many as 500 different genes, including the gene for TNF receptor 1 (TNFR1). This receptor is embedded in the cell membranes of most body cells, where it receives signals for TNF and transmits signals that trigger an inflammatory response. The inflammatory signal can be turned off by removing the TNF receptor from the cell's surface, a process called "shedding." The portion that is released can suppress the inflammatory response by absorbing TNF before it reaches cells to transmit its signal. Even before TNFR1 was known to be located in the target region of chromosome 12, the Nottingham team had found low levels of soluble TNFR1 in the blood of Hibernian fever patients.
McDermott worked with Dr. Ivona Aksentijevich in Kastner's laboratory to screen the TNFR1 gene for sequence differences between patient and normal groups. On Thanksgiving Day, 1998, they found the first unmistakable changes in the DNA sequence. Ultimately, the collaborators found six disease-associated mutations. Because these mutations were found in families of several different ethnic backgrounds, the authors proposed the more neutral acronym TRAPS to include all of the families.
Drs. Jéröme Galon and John O'Shea, colleagues of Kastner's, have studied how these mutations cause disease. In a Louisiana family with TRAPS who were patients at NIAMS, they found that the TNFR1 mutation prevented normal shedding of receptor after cellular activation. This could result in prolonged signaling by TNF at the cell surface, and diminished soluble TNFR1 in the blood to absorb TNF and block signaling.
Based on this analysis, Kastner and his colleagues believe that a synthetic form of TNF receptor might help to suppress the inflammation these patients experience. Fortuitously, a drug recently approved for the treatment of rheumatoid arthritis is in fact the shed form of a related TNF receptor. Researchers will now determine the potential usefulness of this drug in treating TRAPS. Currently, many patients are treated with high doses of steroids, which can have serious side effects and are not completely effective.
Kastner expressed hope that the discovery of TNFR1 mutations will help TRAPS patients. "It is absolutely incredible to live in a time when we have the tools to find the exact molecular cause of a baffling disease, and then to be able to do something about it," observes Kastner. "It's such a privilege to have this opportunity."
McDermott, et al. Germline mutations in the extracellular domains of the 55 kDa TNF Receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97: 133-144, 1999.