Discover Genetic Mutations
An international team of researchers has discovered genetic mutations underlying a newly recognized group of inherited inflammatory disorders. These illnesses, one of which was first described in a family of Irish and Scottish descent, are characterized by dramatic, sometimes month-long 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 a potentially fatal complication called amyloidosis, a disease in which there is deposition of a blood protein in vital organs.
Results of the study are published as the lead article in the April 2 issue of the journal Cell. Patients from seven different families with symptoms of these disorders were found to have mutations in a cell surface receptor for an inflammatory protein called tumor necrosis factor (TNF). Normally this receptor plays a role in the body's defenses against infectious and foreign agents. The Cell article explains that mutations in the receptor are responsible for a predisposition to severe inflammation triggered by daily life events such as emotional stress, minor trauma, or for seemingly no apparent reason. This discovery marks the first time that TNF receptor mutations have been tied to an inherited disease.
"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 Dr. Stephen I. Katz, Director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) in Bethesda, Maryland.
The senior author of the report is Dr. Daniel Kastner, a physician-scientist in the Intramural Research Program of NIAMS. Almost two years ago Kastner had successfully led an international consortium in the cloning of the gene for familial Mediterranean fever (FMF), another hereditary disorder of fever and inflammation that is common among people of Jewish, Arab, Armenian, and Turkish ancestry.
After the FMF gene was identified, it became clear that some families with periodic fevers do not have these FMF mutations. Several of these families have been noted to show a dominant mode of inheritance (FMF is recessive), and are not of Mediterranean ancestry. The symptoms most frequently reported by the affected individuals include fever lasting a week or more, accompanied by red and swollen eyes, migratory skin rashes, muscle tenderness, joint pain, and sometimes abdominal or chest pain. An unusually high incidence of inguinal hernia has been noted in affected men. Some patients also develop amyloidosis, which can be fatal.
One of the best-characterized families is of Irish and Scottish ancestry, and was first described by a research team at the Queen's Medical Centre in Nottingham, England. To contrast this condition from FMF and emphasize the Irish ancestry, they named it familial Hibernian fever (FHF). However, families with similar complaints have 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 one year ago when two research teams independently identified a region of chromosome 12 associated with susceptibility to this form of periodic fever. One research team was headed by Dr. Michael McDermott, of the Royal London School of Medicine, formerly a postdoctoral fellow in Kastner's lab. The second team is in Adelaide, Australia, and subsequently a third team of researchers in Helsinki extended these results to a large Finnish family.
At a meeting hosted by Dr. Kastner last year, these research teams and scientists from Cork, Ireland, agreed to collaborate to determine which particular gene on chromosome 12 causes periodic fevers. The target region contained as many as 500 different genes, and the group prepared for a lengthy search. Among the possibilities was the gene for the TNF receptor 1 (TNFR1). This receptor is found embedded in the cell membranes of most cells in the body, where it acts as the transponder for TNF by receiving and transmitting signals that trigger an inflammatory response. The inflammatory signal can be turned off by removal of the TNF receptor from the surface of the cell, 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 group had found low levels of soluble TNFR1 in the blood of Hibernian fever patients.
McDermott worked with Dr. Ivona Aksentijevich in the Kastner 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 consortium found six disease-associated mutations. Because these mutations were found in families of several different ethnic backgrounds, the authors have proposed the more neutral acronym TRAPS (TNF Receptor-Associated Periodic Syndrome) to include all of the families.
Drs. Jérôme 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, these researchers 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 the treatment of TRAPS. Currently, many patients are treated with high doses of steriods, which can have serious side-effects and are not completely effective.
The photo on the cover of the journal shows massive deposits of amyloid in kidney of a patient who died of TRAPS. Kastner expressed hope that the discovery of TNFR1 mutations will help this patient's sister, niece, and 8 year-old daughter to avoid a similar fate. "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."
The National Institute of Arthritis and Musculoskeletal and Skin Diseases leads the Federal biomedical research effort on rheumatic diseases by conducting and supporting research projects, research training, clinical trials, and epidemiologic studies, and through dissemination of health information and research results.
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Reference: McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, Mansfield E, Gadina M, Karenko L, Pettersson T, McCarthy J, Frucht D, Aringer M, Torosyan Y, Teppo A-M, Wilson M, Karaarslan HM, Wan Y, Todd I, Wood G, Schlimgen R, Kumarajeewa TR, Cooper SM, Vella JP, Amos CI, Mulley J, Quane KA, Molloy MG, Ranki A, Powell RJ, Hitman GA, O'Shea JJ, Kastner DL. 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.
Note: first authors Ivona Aksentijevich and Jérôme Galon of the NIAMS, and Michael McDermott of St. Bartholomew's and the Royal London Hospital School of Medicine and Dentistry contributed equally to this work. The senior author is Dr. Daniel L. Kastner.
Portions of this work were supported by the Research Advisory Committee of the Special Trustees, the Royal London Hospitals NHS Trust; the Jones Charitable Trust, Nottingham, UK; the National Health and Medical Research Council of Australia; and the Medical Research Funcs of Tampere and Helsinki University Hospitals, Tampere and Helsinki, Finland.