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.
Schaner
Philip E
PE
University of Michigan, Department of Cell and Developmental Biology, Ann Arbor, MI 48109-0616, USA.
Gumucio
Deborah L
DL
D016207:Cytokines / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology; D010505:Familial Mediterranean Fever / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology*; D018836:Inflammation Mediators / Q000502:physiology; D000071198:Pyrin; D015398:Signal Transduction / Q000502:physiology*
D016207:Cytokines; D003598:Cytoskeletal Proteins; D018836:Inflammation Mediators; C000604192:MEFV protein, human; D000071198:Pyrin