Familial Mediterranean Fever in the Post-Genomic Era: How an Ancient Disease is Providing New Insights into Inflammatory Pathways

Familial Mediterranean fever (FMF, MIM24900), described as a clinical entity only slightly over a half-century ago, has ancient roots among populations surrounding the Mediterranean basin. It is the most prevalent of the hereditary periodic fever syndromes, a group of disorders characterized by episodic attacks of fever and inflammation. Seven years ago, it was discovered that FMF is caused by mutations in MEFV, a gene that encodes a protein variously called pyrin or marenostrin. As exciting as that discovery was, physicians and patients alike were disappointed that the protein sequence of pyrin/marenostrin did not immediately suggest clues as to the molecular etiology of FMF. Though we are still far from a complete understanding of the function of pyrin/marenostrin at the cellular level, continued study of this intriguing protein is revealing new molecular details about inflammatory processes; the emerging information is relevant not only to FMF, but to innate immunity in general. Data from several laboratories demonstrate that pyrin/marenostrin is intimately connected to three important cellular pathways: apoptosis, cytoskeletal signaling and cytokine secretion. These connections occur, at least in part, through the direct interaction of the pyrin/marenostrin protein with two cytosolic protein adaptors: ASC (also called PyCARD or Tms1) and PSTPIP (also called CD2BP1). Here, we review the more recent literature regarding the molecular and cellular biology of pyrin/marenostrin and pinpoint open questions for future study.