Familial Mediterranean fever (FMF) is an autosomal recessive disease frequently seen in non-Ashkenazi Jews, Arabs, Armenians, and Turks. The main clinical features include periodic attacks of fever and serositis, sometimes complicated with amyloidosis. The gene mutated in this disease, MEFV, has been cloned and five different missense mutations have been identified in affected individuals, in the last exon of the gene. MEFV encodes a 3.7 kb transcript that is almost exlusively expressed in granulocytes. The encoded protein, pyrin, is a member of a family of proteins homologous to the Ro52 autoantigen. The function of pyrin is still unclear. It is likely that pyrin plays an important role in the inflammatory and immune response functions of mature granulocytes. We propose to study the function of pyrin by generating mice with either deletions or missense mutations (mimicking those in FMF patients) in the mouse MEFV gene, using standard gene targeting techniques. Phenotypes, especially changes in the maturation of granulocytes and their inflammatory and immune responses will be recorded and analyzed. The expression pattern of the gene will also be studied by RNA in situ hybridization and by generating transgenic mice with the lacZ gene under the control of MEFV promoter.
