Familial Mediterranean Fever in the Genes: Blame Noah's Offspring
ABSTRACTS & COMMENTARY
Synopsis: Familial Mediterranean fever is associated with mutations in a gene encoding a neutrophil protein called pyrin that is believed to normally antagonize the inflammatory response.
Sources: Pras M. Familial Mediterranean fever: From the clinical syndrome to the cloning of the pyrin gene. Scand J Rheumatol 1998;27:92-97; Ben-Chetrit E, Levy M. Familial Mediterranean fever. Lancet 1998;351: 659-664.
Familial mediterranean fever (fmf) is an intermittently manifested disease affecting individuals of Middle Eastern origin that is genetically transmitted as an autosomal recessive trait. Episodes of illness, which usually begin in childhood, are characterized by high fever and serositis causing abdominal, pleuritic, and/or joint pain. Patients may also manifest painful skin lesions that resemble Serysipelas. During attacks, which usually last 1-3 days, the white blood cell count and erythrocyte sedimentation rate are elevated, but no specific diagnostic test has been available. The interval between attacks is highly variable, irregular, and unpredictable, varying from weeks to years. Some patients develop type AA amyloidosis, initially manifested by nephrotic-level proteinuria. Colchicine prophylaxis is effective in completely or partially preventing episodes of disease and may decrease the risk of amyloidosis.
FMF, while predominantly affecting people of Jewish (non-Ashkenazi), Armenian, and Turkish origin, also affects Arabs, Druze, and Assyrians. The genetic nature of the disease was confirmed in 1992 when the putative FMF gene was mapped to chromosome 16.1 In 1997, two groups of investigators reported the identification of five individual mutations of the FMF gene in various ethnic groups-mutations that were absent in a large number of normal controls. The five missense mutations all occurred in the tenth of the 10 exons of the gene, which is called pyrin (although the French investigators, in their inimitable fashion, call it marenostrin- "our sea").2,3
Examination of various tissues by a hybridization probe led to the conclusion that the pyrin gene seems to be expressed only in polymorphonuclear leukocytes. This and other observations have led the investigators to believe that the wild type 781 amino acid pyrin protein probably functions, directly or indirectly, as an inhibitor of inflammation. Thus, in the presence of the defective mutant protein, triggering of inflammation by any of a variety of events occurring in everyday life leads to attacks of FMF as a result of unconstrained inflammation.
One of the five identified mutations are present in 80% of patients or carriers of FMF, indicating that additional mutations await detection. Analysis of four of the mutant genes led to the conclusion that they pointed to "an ancient common founder . . . in one of the sons of Shem."
COMMENT BY STAN DERESINSKI, MD, FACP
FMF has always seemed, to me, a somewhat mysterious disease to me, much more familiar to members of our local Armenian community than to most physicians. This review by Mordechai Pras at the Chaim Sheba Medical Center in Israel, provides an excellent overview of the epidemiology and clinical manifestations of the disease, as well as a discussion of the recent discovery of the pyrin gene and mutations of this gene associated with FMF.
Further work remains to be done, including experimental demonstration of the function of the wild type pyrin protein as well as a demonstration that the observed mutations disrupt this function. Homology analyses suggest that pyrin may be a transcription factor. If so, it can be surmised that it acts by regulating the expression of other genes involved in the suppression of the inflammatory response. Some investigators have suggested that pyrin upregulates the synthesis of a chemotactic inactivator.4
Discovery of the mutant genes associated with FMF provide an important tool for genetic counseling and, potentially, a diagnostic test for FMF. It may also open up further understanding of the pathogenesis of amyloidosis. Finally, a path to the development of genetic and drug therapies of this disease has also now been defined.
The observation that the pyrin gene mutations associated with FMF have their origin in a common founder among the sons of Shem led me to a copy of the New English Bible. Shem was a son of Noah; his descendants are the Semites. The descendants of the sons of Noah, including those of Shem-Elam, Ashur, Arphaxad, Lud and Aram- "spread over the whole earth." "Shem was a hundred years old when he begot Arphaxad, two years after the flood. After the birth of Arphaxad he lived five hundred years, and had other sons and daughters."5 And thus came FMF.
References
1. Pras E, et al. Mapping of a gene causing familial Mediterranean fever. N Engl J Med 1992;326: 1509-1513.
2. The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 1997;90:797-807.
3. The French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet 1997;17: 25-31.
4. Babior BM, Matzner Y. N Engl J Med 1997;337: 1548-1549.
5. Genesis 9:19, 10:221-22, 11:10-11.
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