Disease relevance of MEFV

• Renal amyloidosis, prevented by colchicine, is the most severe complication of FMF, a disorder associated with mutations in the MEFV gene [1].
• Analysis of complementary DNA from human solid tumor-derived cell lines revealed expression of MEFV in several cell lines derived from colon and prostate cancers [2].
• Eight of the common familial Mediterranean fever (FMF) gene MEFV mutations were excluded [3].
• This is the second Th1-type autoimmune disease in which MEFV mutations have been shown to aggravate the clinical status [4].
• METHODS: We studied 16 patients with FMF during an attack of acute peritonitis and 17 otherwise healthy individuals who were undergoing surgery because of acute appendicitis [5].

Psychiatry related information on MEFV

• The M694V variant of the familial Mediterranean fever gene is associated with sporadic early-onset Alzheimer's disease in an Italian population sample [6].
• METHODS: Patients with CFS (n=40), non-CFS chronic fatigue (n=73), fibromyalgia (n=41), neurally mediated syncope (n=58), generalized anxiety disorder (n=28), familial Mediterranean fever (n=50), arterial hypertension (n=28), and healthy subjects (n=59) were evaluated with a standardized head-up tilt test (HUTT) [7].
• This study tested the relationship between psychosocial factors and incidence of Familial Mediterranean Fever (FMF) attacks [8].

High impact information on MEFV

• The N-terminal domain consists of transactivation, CARD, Pyrin, or BIR domains, with a minority containing undefined domains [9].
• Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome [10].
• Familial Mediterranean fever (FMF; MIM 249100) is an autosomal recessive disease characterized by recurrent attacks of fever with synovial, pleural or peritoneal inflammation [11].
• Human population studies have revealed extremely high allele frequencies for several different pyrin mutations, leading to the conclusion that the mutant alleles confer a selective advantage [11].
• Familial Mediterranean fever is an autosomal-recessive disease characterized by acute attacks of fever with sterile peritonitis, pleurisy, or synovitis [12].

Chemical compound and disease context of MEFV

• PSTPIP1, mutated in the syndrome of pyogenic arthritis with pyoderma gangrenosum and acne, interacts both with pyrin and a protein tyrosine phosphatase to regulate innate and adaptive immune responses [13].
• Spirometry, body plethysmography, maximal expiratory flow-volume curves (MEFV-curves) with air and with heliox (80% He + 20% O2) before and after inhalation of bronchodilators were studied in a group of 20 adult cystic fibrosis (CF) patients [14].
• We have previously demonstrated an altered pattern of tumor necrosis factor (TNF) secretion in patients with familial Mediterranean fever (FMF) [15].
• A 42-year-old familial Mediterranean fever (FMF) patient who was treated with cisplatin-based chemotherapy for adenocarcinoma of the lung developed severe and frequent attacks of FMF during treatment [16].
• Retrospective analysis of data abstracted from the charts of all 68 FMF patients with amyloidosis who presented during the study period (1974-1992) with proteinuria (> or = 0.5 gm/24 hours) and creatinine values < or = 2.5 mg/dl, received colchicine, and were followed up for > or = 5 years [17].

Biological context of MEFV

• This association, which was present whatever the MEFV genotype, was extremely marked in patients homozygous for M694V (11/11) [18].
• The presence of three frequent MEFV mutations in multiple Mediterranean populations strongly suggests a heterozygote advantage in this geographic region [19].
• To evaluate the diagnostic and prognostic value of MEFV-gene analysis, we investigated 90 Armenian FMF patients from 77 unrelated families that were not selected through genetic-linkage analysis [1].
• Consistent with the tissue specificity of expression, complete sequencing and analysis of upstream regulatory regions of MEFV revealed homology to myeloid-specific promoters and to more broadly expressed inflammatory promoter elements [20].
• Here, we describe the isolation and expression of a novel human MEFV isoform, MEFV-d2, generated by in-frame alternative splicing of exon 2 [21].

Anatomical context of MEFV

• MEFV messenger RNA was detected by reverse transcriptase-polymerase chain reaction in bone marrow leukocytes, with differential expression observed among cells by in situ hybridization [20].
• MEFV is expressed preferentially in granulocytes and myeloid bone marrow precursors, giving rise to speculation that the protein may serve as a transcriptional regulator of inflammation in granulocytes [22].
• The prepromyelocytic cell line HL60 expressed MEFV only at granulocytic and monocytic differentiation [20].
• Taken together, MEFV is predominantly expressed in myeloid cells and upregulated during myeloid differentiation, and the corresponding protein, pyrin, is expressed in the cytoplasm [2].
• Reverse transcription-polymerase chain reaction analysis, followed by hybridization with an internal oligonucleotide, demonstrated expression of MEFV in different populations of peripheral blood cells [2].

Associations of MEFV with chemical compounds

• Furthermore, MEFV messenger RNA was strongly expressed within 24 hours of dimethyl sulfoxide-induced granulocytic differentiation of HL-60 cells [2].
• The Y344F PSTPIP1/CD2BP1 mutation, which blocks tyrosine phosphorylation, was associated with a marked reduction in pyrin binding in pervanadate-treated cells [23].
• Tumor necrosis factor in familial Mediterranean fever [24].
• Specific glycosylation of alpha(1)-acid glycoprotein characterises patients with familial Mediterranean fever and obligatory carriers of MEFV [25].
• The TNF-alpha, IL-1beta, and IL-6 content in supernatants derived from LPS stimulated blood cells was not modified by the attacks of FMF [26].

Physical interactions of MEFV

• BRCA1 (aa 502-802) interacted with the IFI16 Pyrin domain (aa 1-130) [27].
• A poxvirus-encoded pyrin domain protein interacts with ASC-1 to inhibit host inflammatory and apoptotic responses to infection [28].

Co-localisations of MEFV

• Immunofluorescence studies show that pyrin co-localizes with ASC in specks [29].

Regulatory relationships of MEFV

• IFN-alpha also induced MEFV expression [20].
• In granulocytes, MEFV was up-regulated by IFN-gamma and the combination of IFN-alpha and colchicine [20].
• MEFV was also expressed in other cell lines that do not produce C5a/IL-8 inhibitor [30].
• MEFV was expressed in peritoneal and skin fibroblasts at a lower level than in neutrophils and could be further induced by PMA and IL-1 beta [30].

Other interactions of MEFV

• PAPA-associated A230T and E250Q PSTPIP1/CD2BP1 mutations markedly increased pyrin binding as assayed by immunoprecipitation and, relative to WT, these mutants were hyperphosphorylated when coexpressed with c-Abl kinase [23].
• Disease severity was mainly influenced by MEFV mutations and was not associated with genotypes at the SAA1 locus [31].
• Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)/target of methylation-induced silencing/PYCARD represents one of only two proteins encoded in the human genome that contains a caspase recruitment domain (CARD) together with a pyrin, AIM, ASC, and death domain-like (PAAD)/PYRIN/DAPIN domain [32].
• RESULTS: Linkage to both TNFRSF1A and MEFV was definitively excluded, and DNA sequencing of these genes revealed no mutations [33].
• Severe disease in patients with rheumatoid arthritis carrying a mutation in the Mediterranean fever gene [4].

Analytical, diagnostic and therapeutic context of MEFV

• The glycosylation of AGP in the MEFV carrier group, compared with that in a healthy control group, was characterised by a significant increase (p<0.05) in branching of the glycans, whereas the fucosylation remained unaffected [25].
• METHODS: Mutations of the MEFV and TNFRSF1A genes, responsible respectively for FMF and TRAPS, were searched for by amplifying, using polymerase chain reaction (PCR), genomic DNA, and direct sequencing [34].
• Semi-quantitative RT-PCR assays enabled estimation of MEFV induction by the cytokines at 10-100-fold and could not be further increased by concomitant addition of colchicine [35].
• We sought additional upstream regulators of inflammation by using pyrin as the bait in yeast two-hybrid assays [23].
• OBJECTIVES: To identify the ethnic, clinical, genetic, and pharmacokinetic correlates of colchicine treatment failure in patients with familial Mediterranean fever (FMF) [36].

References