NIH Leads International Group that Identifies Gene for Familial Mediterranean Fever Mutations Date Back to Biblical Times

National Institute of Arthritis and, Musculoskeletal and Skin DiseasesEMBARGOED FOR RELEASE, Thursday, August 21, 1997, 5:00 PM Eastern Time, Elia Ben-Ari, [email protected]

An international consortium of researchers, led by investigators at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), has for the first time identified the gene for familial Mediterranean fever (FMF) and found three different gene mutations that cause this inherited rheumatic disease. The gene holds the code for making a protein the researchers call pyrin. They hypothesize that pyrin normally plays a role in keeping inflammation under control, and that mutations in the gene lead to a malfunctioning protein and uncontrolled inflammation.

Discovery of the gene mutations, published in the August 22 issue of Cell, "will allow immediately a simple diagnostic blood test for FMF," says lead researcher Daniel L. Kastner, M.D., Ph.D. "One reason that's important is that in the U.S. physicians are often unfamiliar with FMF. Now it will be possible to develop a simple diagnostic test for FMF that could be used in patients with unexplained, recurring fevers," says Kastner, who heads a lab in the Arthritis and Rheumatism Branch at the NIAMSpart of the National Institutes of Health (NIH), in Bethesda, Md. Researchers hope that studying how pyrin works will ultimately lead to new, improved treatments for FMF and perhaps for other diseases involving excess inflammation.

People with FMF suffer from recurring bouts of fever, most commonly with severe abdominal pain due to inflammation of the abdominal cavity (peritonitis). Attacks can also include arthritis (painful, swollen joints), chest pain from inflammation of the lung cavity (pleurisy), and skin rashes. Some patients develop amyloidosis, a potentially deadly buildup of protein in vital organs such as the kidneys. The only treatment for FMF is a drug called colchicine, which patients have to take every day for life and which causes side effects such as diarrhea and abdominal cramps.

FMF occurs most commonly in people of non-Ashkenzi Jewish, Armenian, Arab and Turkish background living in the U.S. and abroad. As many as 1 in 200 people in these populations have the disease, and as many as 1 in 5 to 1 in 7 carry a mutated FMF gene. A person must inherit two mutated copies of the geneone from each parentin order to get FMF.

Kastner's research group identified the gene for FMF after years of searching, with the collaboration of researchers from four other U.S. groups, including the National Human Genome Research Institute at NIH, as well as investigators from Israel and Australia. In their quest for the disease gene, the researchers analyzed genetic material from people in 62 families with FMF, most of them recruited through clinics in Tel Aviv and Los Angeles. Out of the three FMF gene mutations identified so far in these families, the same two mutations are found in ethnic populations that have been geographically separated for over 2,000 years, suggesting that most individuals with the disease are descended from a small, ancient group of individuals.

The three gene mutations found to date lead to changes in the same region near one end of the protein, suggesting that this region is critical to pyrin's function. Computer analyses done by the researchers show that the gene mutations in FMF lead to an alteration in the shape of the pyrin protein. This shape change presumably interferes with pyrin's normal functioning.

The pyrin protein, named from the Greek word for fire, bears a strong resemblance to several proteins found in the nucleus of cells. Some of these proteins are known to regulate inflammation. Kastner and colleagues found that the FMF gene is decoded to make the protein only in white blood cells called peripheral blood leukocytes, which are the first line of the body's defense system in an infection or after certain other challenges to the body. In attacks of FMF, these leukocytes rush into the affected part of the body in massive numbers, triggering inflammationa typical response of tissues to injury or disease that is characterized by redness, swelling, heat and pain.

The researchers think that pyrin may normally act as a switch to shut down or dampen the inflammatory reaction. In FMF, Kastner hypothesizes, "this switch is not working quite right, so that even if you get a small provocation you can end up getting a strong inflammatory response, whereas in normal people the protein would [eventually] shut down this response." This over-reaction leads to disease symptoms such as fever and excessive inflammation.

The fact that mutations in the FMF gene are so common in several Middle Eastern populations suggests that people with only one mutated FMF genewho are carriers for the disease but do not have FMFmay have some type of survival advantage. For example, says Kastner, they may have an increased resistance to one or more disease-causing organisms, perhaps ones that are very common in the Mediterranean region.

Kastner and colleagues have results suggesting that one particular mutation tends to be associated with more severe disease. "It may be that as we start to understand these mutations one could determine a bit more about the prognosis of a given individual, based on their specific mutation," Kastner says. If doctors could identify those people at high risk for developing amyloidosis, the potentially fatal complication of FMF, they could make sure that those patients stayed on their medication and could in many cases prevent development of amyloidosis. Many patients choose to stop taking colchicine for various reasons, including the drug's side effects.

One intriguing finding from these studies is the evidence that FMF mutations date back to Biblical times. The evidence for this is partly historical, says Kastner, and comes from comparing populations known to have been geographically separated for long periods of time. For example, some members of the Iraqi Jewish population have the same FMF gene mutation as the North African Jewish population. This suggests the mutation arose in some common ancestors of these two groups before they separated about 2,500 years ago.

Historical interests aside, identifying the genetic cause of FMF is in some ways just the beginning of the story. The researchers now must pursue work such as looking at the minority of patients in whom they have not yet found mutations, and studying the pyrin protein to better understand the role it plays under normal circumstances and in people with FMF. "The longer-term payoff [of this work] is in terms of therapeutics," Kastner says. "Eventually understanding this protein [pyrin] or proteins in this same pathway might give rise to a new class of anti-inflammatory drugs."

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.

Reference: The International FMF Consortium. "Ancient missense mutations in a new member of the RoRet gene family cause familial Mediterranean fever." Cell 90: 797-807, August 22, 1997.

Note: First authors Ivona Aksentijevich, Michael Centola, Zuoming Deng and Raman Sood, of the NIAMS, contributed equally to this work. The senior author is Daniel L. Kastner.

Portions of this work were supported by the Arthritis Foundation, the Cedars-Sinai Board of Governors (Los Angeles, Calif.), the U.S. Department of Energy, and the National Health and Medical Research Council of Australia.

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