Alt. symbols: MEF | FMF | TRIM20

Approved name: MEFV innate immunity regulator, pyrin
Alt. names: Mediterranean fever, MEFV, pyrin innate immunity regulator | marenostrin

Location: 16p13.3: 3242027 - 3256633 (-)
Gene type: protein_coding, 15 transcripts.

Scores: LoFtool: 0.912000 | pLI: 0.00000001 | LOEUF: 1.129

HGNC: 6998

NCBI: 4210, RefSeq: NG_007871.1

Ensembl: ENSG00000103313.14

LRG_190 | Status: public

OMIM: 608107

Expression | ProteinAtlas

The MEFV gene encodes a protein called pyrin (also known as marenostrin) that appears to have structural functions within the cell's cytoskeleton, helping to define the cell's shape, size, and movement. Pyrin belongs to the family of cytosolic pattern recognition receptors (PRRs) and is an important regulator of innate immunity, crucial for the ability of certain white blood cells, such as neutrophils, eosinophils or monocytes, to respond to pathogens by regulating inflammation. This explains the high MEFV expression detected in tissues and organs like bone marrow and lymph nodes, spleen, lungs, and the appendix. Upon the detection of pathogens or PAMPs/DAMPs (pathogen/danger?associated molecular patterns) pyrin may be activated and may promote the assembly of an inflammasome, a multiprotein signalling complex that recruits and activates the protease caspase?1. Active caspase?1 drives inflammation by promoting the proteolytic maturation and secretion of cytokines such as interleukin (IL)?1beta and IL?18, and by initiating a necrotic type of cell death known as pyroptosis (Heilig and Broz, 2018). Pyrin's interaction with the cytoskeleton is not fully understood, although it may direct the migration of neutrophils, eosinophils and monocytes to sites of inflammation (in response to IFN-gamma), and stop or slow the inflammatory response (via autophagy) when it is no longer needed; thus keeping the inflammation process under control. During this process, pyrin is involved in the initiation of autophagy by coordinating autophagy target recognition with the assembly of the autophagy apparatus. Pyrin also acts as an autophagy receptor for the degradation of several inflammasome components, including CASP1, NLRP1 and NLRP3, hence preventing excessive IL1beta- and IL18-mediated inflammation. MEFV encodes 2 isoforms of pyrin, a large protein of 781 amino acids (NP_000234) and a shorter one of 445 amino acids (NP_001185465). The larger isoform is the one predominantly expressed and shows cytoplasmic localisation, whereas the shorter isoform (lacks the exon 2) displays nuclear localisation. However, when this shorter isoform binds to the ASC complex (apoptosis-associated speck-like protein containing a CARD), it is translocated to the cytoplasm to participate in ASC speck formation. Pyrin’s main isoform (781 aa.) is structured in different functional domains: it has a pyrin domain (first 92 amino acids), a Box-type Zinc-finger domain (aa. 370-412), a homotrimerization domain (aa. 420-582), and a terminal B30.2/SPRY domain (aa. 580-775). The pyrin domain allows Pyrin to interact with other pyrin domain containing proteins involved in fighting infection and in the inflammatory response. Proteins containing a pyrin domain are frequently involved in processes such as inflammation and apoptosis. These proteins include intracellular microbial sensors (NOD-like receptors), and proteins associated with their function, such as PYCARD and certain fish caspases.

Pathogenic variants in the MEFV gene are known to cause Familial Mediterranean fever (FMF), an autoinflammatory condition characterized by repeated short episodes of inflammation, pain and serositis including fever, peritonitis, synovitis, pleuritis, and, rarely, pericarditis and meningitis. FMF carrier frequencies in the range of 1:3 to 1:5 have been documented in a number of populations, including Jews, Arabs, Turks, Armenians, and Italians, hypothesized to have arisen as a form of heterozygot e advantage in response to plague (PMID: 32601469). The symptoms and severity of the disease vary among affected individuals, even among members of the same family. Amyloidosis is the most severe complication in FMF patients and can lead to renal failure if untreated. The presence of elevated IgD serum levels generally correlate with the severity of the phenotype, and especially with arthritis (PMID: 11781702). There is a form of FMF (type 2 FMF) that is characterized by amyloidosis in an otherwise asymptomatic individual. FMF is inherited in an autosomal recessive manner due to the presence of biallelic MEFV pathogenic variants. However, FMF can also present as an autosomal dominant disease, since up to 25% of individuals with only one mutated MEFV allele develop FMF. Currently, it is not entirely clear what is the total number of pathogenic variants identified in the MEFV gene. According to the latest literature reviews up to 38 pathogenic variants have been reported (PMID: 19790133, 27708867, 28624931). Other specialised databases differ in the number of disease-associated variants in MEFV. The Infevers database has 5 and 48 pathogenic and likely pathogenic variants registered, the LOVD has 25 and 14 respectively, ClinVar has 17 and 2, and VarSome 72 and 3. Nonetheless, they all agree that the vast majority of these disease-associated variants are missense, meaning that they lead to a single-amino acid change on the protein sequence, generating mutant or dysfunctional isoforms of pyrin (the protein encoded by MEFV). As a result, pyrin cannot perform its presumed role in controlling inflammation, leading to an inappropriate or prolonged inflammatory response that may present as fever and inflammation in the abdomen, chest, joints, or skin. The variant p.Met649Val (M694V) is the most commonly identified cause of FMF in affected individuals: it is present in about 47-80% of FMF Jewish patients (of Iraqi and North African descent) (PMID: 9781020, 21290976), in 44.8% of Armenian FMF patients (PMID: 10364520), in 51.6% of Turkish FMF patients (PMID: 11464248), and in 6% of French FMF patients. Besides the M694V variant, the other common pathogenic variants are p.Val726Ala, p.Met694Ile, p.Met680Ile and p.Glu148Gln. All five, are considered founder mutations (PMID: 19790133). These mutations in the C-terminal B30.2/SPRY domain of pyrin perturb ULK1 recruitment and autophagic degradation of inflammasome components, including NLRP3. Among FMF affected individuals, the M649V variant is seemingly associated with an increased risk of developing amyloidosis. Other environmental and genetic factors such as variations in the SAA1 gene can further modify the risk of developing amyloidosis among people with the M694V mutation (PMID: 12563686). Many studies have proposed a link between MEFV variants and IBD – some conceptualize IBD as one of many FMF-associated inflammatory diseases (PMID: 12441897, 17520284, 20306331, 22810105, 23164758, 26078663, 28040706, 313 [Load More]