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

Abstract

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.

The Population Genetics of Familial Mediterranean Fever: A Meta‐Analysis Study

“…These data support the heterozygote advantage hypothesis (Touitou, 2001;Aksentijevich et al, 1999;Schaner et al, 2001). Thus, positive selection pressure favouring heterozygosity of MEFV mutations may reflect the need for better response to intracellular pathogens (Schaner & Gumucio 2005) or protection against diseases that are associated with an increased Th2 activity such as asthma (Sackesen, 2004).…”

Monocyte mRNA Phenotype and Adverse Outcomes From Pediatric Multiple Organ Dysfunction Syndrome

“…Although the specific functions of pyrin are not clear, it is certain that pyrin mutations are responsible for the disease familial Mediterranean fever (FMF) in which patients suffer recurrent bouts of systemic inflammation. This is thought to be the result of one of a number of loss-of-function mutations in the MEFV gene (44,45). Ustek et al (46) recently demonstrated reduced levels of MEFV mRNA in peripheral blood leukocytes from FMF patients who were experiencing active inflammation compared with periods of quiescence.…”

A population genetics study of the Familial Mediterranean Fever gene: evidence of balancing selection under an overdominance regime

“…2,3 Pyrin (or marenostrin), the protein product of MEFV, is a 781-amino acid protein expressed in most types of white blood cells 4 and involved in pivotal cellular processes such as apoptosis, cytoskeletal signaling and cytokine secretion. 5 Although its precise role in inflammatory processes is still unknown, pyrin has been shown to interact with an adaptor protein denoted apoptosis-associated speck-like protein with a CARD through its PYRIN N-terminal domain 6,7 and to regulate caspase-1 activation and IL1-b production. 7 More recently, the C-terminal B30.2 domain of pyrin was demonstrated 8 to directly interact with and inhibit caspase-1, the net result being an attenuation of IL1-b activation.…”