BETHESDA, Md. - An international consortium of researchers -- led by investigators at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the National Human Genome Research Institute (NHGRI) at the National Institutes of Health (NIH) -- have, for the first time, identified a 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. from the NIAMS. "One reason that's important is that in the United States 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," said Kastner.
Researchers hope that studying how pyrin works will ultimately lead to new, improved treatments for FMF and perhaps for other diseases involving excess inflammation.
The FMF gene is one of an increasing list of human disease genes that have been found using the resources of the Human Genome Project (HGP), the multi-year, international effort to map all of the genes in the human body.
"Successful identification of the FMF gene, which was a particularly challenging target because of the subtlety of its mutations, is another example of the way that the tools and technologies of the Human Genome Project have made possible gene discoveries considered impossible only a decade ago," said Francis Collins, M.D., Ph.D., director of the NHGRI. "In this instance, finding the FMF gene may well shed light on the whole mechanism by which the human body mounts an inflammatory response, and may well have spin offs that extend far beyond those individuals with this genetic disorder."
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 United States 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 gene -- one from each parent -- in order to get FMF.
The research groups identified the gene for FMF after years of collaboration with several U.S. groups, as well as investigators from Israel and Australia. 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.
Researchers at NHGRI, including Dr. Francis Collins, Dr. Pu Paul Liu and Trevor Blake of the Laboratory of GeneTransfer, made key contributions to the cloning of the FMF gene by generating a physical map in the study and in the isolation of candidate genes in the region. The NHGRI team made several critical discoveries during screening for gene mutations which ultimately led to the identification of the FMF gene.
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. The researchers 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 inflammation -- a 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 gene -- who are carriers for the disease but do not have FMF -- may have some type of survival advantage such as an increased resistance to one or more disease-causing organisms, perhaps ones that are very common in the Mediterranean region.
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."
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Last Reviewed: July 2006