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MEFV

The MEFV gene encodes pyrin (also known as marenostrin), a 781-amino-acid protein that functions as an innate immunity regulator by modulating inflammasome assembly and controlling inflammatory responses in white blood cells such as neutrophils, monocytes, and eosinophils.^[1]^[2] Located on the short arm of chromosome 16 at cytogenetic band 16p13.3, the gene spans approximately 14.5 kilobases and consists of 10 exons, with expression primarily in granulocytes and other immune cells.^[3] Mutations in MEFV are the primary cause of Familial Mediterranean Fever (FMF), an autosomal recessive autoinflammatory disorder marked by recurrent, self-limited episodes of fever accompanied by serositis (inflammation of the serous membranes lining the abdomen, chest, or joints), often lasting 12 to 72 hours, but also contribute to other pyrinopathies.^[4]^[2] Pyrin plays a critical role in innate immunity by sensing disruptions in Rho GTPase activity—often triggered by bacterial toxins—and forming an inflammasome complex with ASC (apoptosis-associated speck-like protein containing a CARD) and pro-caspase-1, which activates the production of interleukin-1 beta (IL-1β) to mount an inflammatory response.^[2] In healthy individuals, pyrin inhibits excessive caspase-1 activation to prevent unwarranted inflammation, but loss-of-function mutations in MEFV impair this regulation, leading to uncontrolled IL-1β release and periodic inflammatory flares.^[1] Over 80 variants have been identified, with more than 50 confirmed as pathogenic; the most common being M694V (methionine to valine at position 694) in exon 10, which is associated with severe disease phenotypes, high penetrance (up to 99% in homozygotes), and an elevated risk of amyloid A (AA) amyloidosis—a complication that can progress to kidney failure.^[2] Other frequent mutations include V726A and E148Q, which exhibit variable penetrance and contribute to the disorder's phenotypic heterogeneity.^[2] FMF predominantly affects populations of Mediterranean descent, including Armenians, Arabs, Turks, and Jews, with carrier frequencies reaching 1 in 5 to 1 in 7 in these groups and disease prevalence estimated at 1 in 200 to 1 in 1,000.^[4] The condition is inherited in an autosomal recessive manner, requiring biallelic mutations for full expression, though rare autosomal dominant cases or pseudodominance (due to high carrier rates) have been reported.^[4] Symptoms typically onset in childhood or early adolescence, with attacks triggered by stress, infection, or menstruation, and may include erysipelas-like skin rashes, myalgia, or arthritis in addition to the core fever and serositis features.^[4] Without treatment, chronic inflammation can lead to systemic amyloidosis in 25-75% of untreated cases, particularly in severe genotypes.^[2] Diagnosis of FMF relies on clinical criteria such as the Tel Hashomer criteria, combined with genetic testing for MEFV variants, which supports the diagnosis, although up to 25% of clinically diagnosed cases may lack identifiable biallelic pathogenic variants.^[2]^[5] The cornerstone of treatment is colchicine, a microtubule inhibitor that prevents attacks in 60-90% of patients and reduces amyloidosis risk by suppressing pyrin-mediated inflammation.^[4] For colchicine-resistant cases (5-10% of patients), biologic agents targeting IL-1β, such as anakinra or canakinumab, are recommended per 2025 EULAR/PReS guidelines, with efficacy demonstrated in clinical trials and practice.^[2]^[6] Genetic counseling is recommended for at-risk families, given the high carrier rates in affected ethnic groups.^[4]

Gene and Protein

Genomic Location and Structure

The MEFV gene is located on the short arm of chromosome 16 at cytogenetic band p13.3, spanning genomic coordinates 3,242,027 to 3,256,633 on the GRCh38.p14 reference assembly, on the minus strand.^[3] This positions it within a gene-dense region of the genome, flanked by neighboring loci such as TTC39A upstream and NQO1 downstream, contributing to the local chromatin architecture.^[7] The gene itself covers approximately 15 kb, reflecting a compact organization typical of many human genes involved in immune regulation.^[3] Structurally, MEFV comprises 10 exons separated by 9 introns, with exon-intron boundaries defined by consensus splice sites (GT-AG rule) that facilitate precise RNA processing.^[8] Exon 1 contains the 5' untranslated region (UTR) and the beginning of the protein-coding sequence, while exons 2 through 10 complete the coding sequence, with exon 10 being the largest at approximately 1,668 bp and containing much of the C-terminal domain.^[8] Key regulatory elements include a proximal promoter region upstream of exon 1, featuring conserved binding sites for transcription factors NF-κB p65 and C/EBPβ, which enable inducible expression. The primary transcript, NM_000243.3, measures 3,506 nucleotides in length, including 46 bp in the 5' UTR, a 2,346 bp coding sequence, and a 1,114 bp 3' UTR.^[8] Alternative splicing generates multiple isoforms, with at least 16 variants reported; a notable one (NM_001198536.2) skips exon 2, resulting in a frameshift and altered C-terminus that influences subcellular localization.^[9] These variants arise from mutually exclusive exon usage and are confirmed in leukocyte tissues where MEFV is predominantly expressed.^[5] MEFV exhibits strong evolutionary conservation, particularly in its protein-coding regions, reflecting its essential role in innate immunity across mammals. Orthologs show sequence identities of 98.8% with chimpanzee (Pan troglodytes), 72.6% with cow (Bos taurus), 72.2% with dog (Canis lupus familiaris), and 66.5% with mouse (Mus musculus), indicating divergence primarily in non-coding elements.^[10] This conservation underscores the gene's ancient origin, with identifiable homologs in most eutherian mammals but reduced similarity in more distant vertebrates.^[11]

Pyrin Protein Characteristics

The pyrin protein, also known as marenostrin, is the product of the MEFV gene located on chromosome 16 and consists of 781 amino acids with a calculated molecular weight of approximately 86 kDa.^[12] It belongs to the tripartite motif (TRIM) family of proteins, characterized by a modular domain structure that contributes to its regulatory roles.^[12] Pyrin's domain architecture includes an N-terminal PYRIN domain spanning residues 1–92, which facilitates protein-protein interactions; a B-box zinc finger domain from residues 105–151, involved in zinc coordination and structural stability; a coiled-coil domain encompassing residues 157–252, which promotes oligomerization; and a C-terminal B30.2/SPRY domain covering residues 364–781, known for ligand binding specificity.^[12] These domains collectively define pyrin's overall fold and potential for intramolecular regulation.^[13] Post-translational modifications of pyrin include phosphorylation at specific serine residues, notably Ser-208 and Ser-242, within the central helical scaffold region. These phosphorylation events enable binding to 14-3-3 chaperone proteins, which stabilize pyrin in an inactive conformation by preventing oligomerization and maintaining its solubility.^[14] Pyrin exhibits primarily cytoplasmic localization in immune cells such as monocytes and neutrophils, where it associates with the cytoskeleton, although it can translocate to the nucleus in certain cell types like granulocytes and fibroblasts. This dynamic distribution is governed by nuclear localization signals (residues 419–437) and nuclear export signals, facilitating regulated shuttling between compartments.^[12]^[15]

Biological Function

Role in Inflammasome Regulation

Pyrin, encoded by the MEFV gene, functions as an intracellular sensor in the innate immune system, detecting modifications to Rho GTPases induced by bacterial toxins and effectors. Specifically, it recognizes the inactivation of RhoA GTPases, such as glucosylation by Clostridium difficile toxins TcdA and TcdB or GAP-mediated inactivation by Yersinia YopE, which disrupts actin cytoskeleton dynamics and triggers pyrin's activation as part of a "guard" mechanism.^[16] This sensing pathway allows pyrin to monitor pathogen virulence factors that target host Rho GTPases, distinguishing it from other inflammasome sensors that detect microbial nucleic acids or damage-associated patterns.^[17] Upon activation, pyrin assembles into an inflammasome complex by oligomerizing through its central helical domain and recruiting the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) via homotypic interactions between their respective PYRIN domains (PYDs). ASC then facilitates the recruitment and autoactivation of pro-caspase-1 through CARD-CARD interactions, forming large oligomeric structures known as ASC specks. This cascade results in the proteolytic processing of pro-interleukin-1β (pro-IL-1β) and pro-IL-18 into their mature, bioactive forms, as well as cleavage of gasdermin D to induce pyroptotic cell death.^[18] The PYD domain of pyrin is critical for these interactions, enabling the propagation of inflammatory signals in myeloid cells like macrophages and neutrophils.^[17] Pyrin's activity is tightly regulated by phosphorylation to prevent aberrant inflammation. In its resting state, kinases PKN1 and PKN2 phosphorylate pyrin at serine residues 208 and 242 (human numbering), promoting binding to 14-3-3 proteins that sequester pyrin and inhibit inflammasome assembly. Dephosphorylation at Ser242 by protein phosphatase 2A (PP2A) relieves this inhibition, allowing pyrin to oligomerize and initiate the response; conversely, sustained hyperphosphorylation maintains repression.^[19] This phosphorylation-dephosphorylation switch integrates environmental cues, such as Rho GTPase perturbation, with downstream signaling.^[20] Recent studies have shown that pyrin can also be activated by endogenous signals, such as the steroid hormone catabolites pregnanolone and etiocholanolone, which inactivate Rho GTPases independently of pathogens, contributing to autoinflammatory conditions.^[21] The pyrin inflammasome pathway intersects with those of NLRP3 and AIM2 inflammasomes, sharing common downstream effectors like ASC and caspase-1 to amplify cytokine release during coordinated innate immune responses to diverse threats. While pyrin activation remains independent of NLRP3 in certain toxin-driven scenarios, integrated stimulation of multiple inflammasomes can enhance overall IL-1β production and programmed cell death pathways.^[17]^[20]

Expression Patterns and Regulation

The MEFV gene exhibits hematopoietic-specific expression, with high levels observed primarily in myeloid cells such as neutrophils, monocytes, and granulocytes including eosinophils.^[22]^[23]^[24] Among peripheral blood leukocytes, MEFV mRNA is detectable in neutrophils and eosinophils at robust levels, while monocytes show varying but generally elevated expression, particularly upon activation by cytokines.^[23] In contrast, expression is lower in non-myeloid immune cells like B and T lymphocytes, and minimal in non-hematopoietic tissues such as fibroblasts and epithelial cells, where it is detected only at trace levels in certain contexts like synovial or skin fibroblasts.^[22]^[25] This pattern underscores MEFV's role in innate immune responses, as pyrin contributes to inflammasome assembly in these cell types.^[23] During development, MEFV expression is upregulated specifically during myeloid differentiation, marking the commitment to granulocytic and monocytic lineages.^[26] In models like the HL-60 promyelocytic cell line, MEFV mRNA becomes detectable within hours of induction toward granulocytic differentiation (e.g., with DMSO) and peaks at 48 hours, remaining absent in undifferentiated states.^[22] Similarly, monocytic differentiation in cell lines such as U937 and THP-1 triggers robust MEFV transcription, aligning with the gene's restriction to mature myeloid cells involved in inflammation.^[23] This temporal regulation ensures pyrin availability coincides with the maturation of immune effector cells. Transcriptional regulation of MEFV is mediated by key elements in its promoter, including binding sites for nuclear factor kappa B (NF-κB) p65 and CCAAT/enhancer-binding protein beta (C/EBPβ).^[27] These factors synergistically activate MEFV in response to proinflammatory stimuli like tumor necrosis factor alpha (TNFα), with the NF-κB site at position -163 and C/EBPβ site at -55 within a 243-bp proximal promoter region sufficient for inducible expression.^[28] Epigenetic control further modulates MEFV through DNA methylation at the exon 2 CpG island, where higher methylation levels correlate negatively with mRNA abundance (correlation coefficient -0.29 overall, P=0.041), potentially silencing transcription in a subset of cells.^[24] Post-transcriptional regulation of MEFV involves microRNAs (miRNAs) that influence mRNA stability and translation in the context of inflammatory diseases like familial Mediterranean fever (FMF).^[29] For instance, miR-155 is differentially expressed in FMF patients and contributes to modulating inflammatory pathways, though its direct impact on MEFV transcripts requires further elucidation; related miRNAs like miR-197-3p have been shown to affect downstream inflammasome components.^[30] Additionally, alternative splicing and nonsense-mediated decay mechanisms process MEFV transcripts, fine-tuning protein levels in myeloid cells.^[24]

Pathophysiology

Common Mutations and Variants

The MEFV gene, located on chromosome 16p13.3, harbors several recurrent mutations that are predominantly missense variants affecting the pyrin protein. Among these, the most frequent are M694V (c.2080A>G in exon 10), V726A (c.2177T>C in exon 10), M680I (c.2040G>C in exon 10), and E148Q (c.442G>C in exon 2). These mutations account for the majority of pathogenic alleles identified across diverse populations, with over 400 sequence variants reported in total.^[31] Carrier frequencies for MEFV variants are elevated in Mediterranean and Middle Eastern populations, approximately 15-25% in Armenians, Turks, Arabs, and various Jewish subgroups, reflecting historical selective pressures.^[32]^[33] These high frequencies underscore the gene's prevalence in regions with shared ancestry, though penetrance varies.^[34] MEFV variants are classified according to American College of Medical Genetics and Genomics guidelines, with many categorized as pathogenic or likely pathogenic based on functional evidence and population data from databases like ClinVar. For instance, M694V, V726A, and M680I are consistently deemed pathogenic due to their association with altered protein function, whereas E148Q is often classified as a variant of uncertain significance or likely benign, as it may represent a common polymorphism without strong disease causality. Benign polymorphisms, such as certain intronic changes, do not disrupt protein integrity and occur at low frequencies globally.^[5] At the molecular level, pathogenic MEFV mutations typically induce gain-of-function effects on the pyrin protein, leading to protein misfolding, impaired oligomerization, or disrupted phosphorylation sites. The M694V variant, located in the B30.2 domain encoded by exon 10, exemplifies this by altering homotypic interactions and regulatory binding, thereby destabilizing the protein's autoinhibitory conformation. Similarly, V726A and M680I in the same domain compromise pyrin's ability to sense microbial signals properly, while E148Q in the PYRIN domain may subtly affect nucleotide binding without severe structural perturbation. These changes collectively impair the protein's regulatory role in inflammasome assembly.^[5]^[35]^[13] Haplotype analyses reveal strong founder effects for these mutations within specific ethnic groups, indicating ancient origins and population bottlenecks. For example, the M694V mutation is linked to a shared haplotype in Armenians, Turks, and North African Jews, tracing back approximately 2,500 years, while V726A shows founder patterns in Ashkenazi Jews and Arabs. E148Q appears on multiple haplotypes across groups, suggesting recurrent origins rather than a single founder event. These associations highlight how genetic drift and migration have shaped variant distribution.^[36]^[37]^[38]

Impact on Innate Immunity

Mutations in the MEFV gene, which encodes the pyrin protein, disrupt innate immune homeostasis primarily through gain-of-function effects that promote excessive inflammasome activation, rather than loss-of-function as previously debated.^[39] Early uncertainty arose from conflicting models, but functional studies have established that common pathogenic variants, such as M694V, act as hypermorphic alleles that lower the activation threshold of the pyrin inflammasome, leading to dysregulated inflammatory responses even in heterozygous carriers.^[40] This shift favors constitutive or pathogen-independent inflammasome assembly, amplifying innate immune signaling and contributing to autoinflammatory states.^[41] The core mechanism involves failure of inhibitory phosphorylation on pyrin, which normally maintains an inactive state by binding regulatory proteins like 14-3-3. MEFV mutations impair this phosphorylation at key serine residues (e.g., S208 and S242), preventing 14-3-3 association and allowing spontaneous dephosphorylation by kinases such as PKN1/2, thereby enabling unchecked inflammasome oligomerization and caspase-1 activation.^[42] Additionally, these variants disrupt Rho GTPase modification sensing and microtubule-dependent regulation, further sensitizing pyrin to low-level stimuli and bypassing safeguards against spurious activation.^[43] As a result, innate immune cells like monocytes and neutrophils exhibit heightened responsiveness, perpetuating a cycle of unresolved inflammation. Dysregulated cytokine production is a hallmark consequence, with mutations driving excessive release of IL-1β and IL-18 through hyperactive caspase-1 processing.^[44] This overproduction sustains systemic inflammation, elevating serum amyloid A (SAA) levels and promoting secondary amyloid deposition in tissues as a byproduct of chronic activation.^[45] Such cytokine dysregulation not only amplifies acute responses but also fosters a pro-inflammatory milieu that impairs immune resolution. At the cellular level, MEFV mutations enhance neutrophil activation, increasing surface expression of adhesion molecules like CD11b and boosting responsiveness to endotoxins, which exacerbates tissue infiltration during inflammatory episodes.^[46] Paradoxically, neutrophils from affected individuals show accelerated apoptosis, both spontaneous and induced, potentially reflecting a compensatory mechanism to limit damage, though this may contribute to inefficient clearance and prolonged inflammation in inflammatory cells.^[47] In heterozygous carriers, who often remain asymptomatic, environmental triggers such as infections, emotional stress, or fatigue can unmask variant effects by providing secondary signals that tip the balance toward inflammasome activation, highlighting the role of gene-environment interactions in innate immune dysregulation.^[48]

Associated Diseases

Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder primarily caused by biallelic pathogenic variants in the MEFV gene, leading to recurrent episodes of fever and serositis.^[5] It manifests as self-limited attacks of inflammation affecting the serosal membranes, joints, and skin, typically beginning in childhood and resolving spontaneously within hours to days.^[32] The disease is most prevalent among populations of Mediterranean and Middle Eastern descent, where it imposes a significant health burden due to potential complications like amyloidosis if untreated. The core clinical features of FMF include recurrent fevers ranging from 38°C to 40°C, lasting 12 to 72 hours, often accompanied by serositis manifesting as peritonitis (abdominal pain in ~90% of cases), pleuritis (chest pain in ~45%), or synovitis (joint pain in ~75%).^[5] Additional symptoms may involve an erysipelas-like rash on the lower extremities, characterized by tender, red lesions that resolve without scarring.^[32] Attacks are frequently triggered by factors such as stress, menstruation, infections, or physical exertion, with episodes recurring every few weeks to months and varying in intensity. Epidemiologically, FMF exhibits a prevalence of 1:200 to 1:1,000 in high-risk ethnic groups, including non-Ashkenazi Jews, Arabs, Turks, Armenians, and other Mediterranean ancestries, with carrier frequencies reaching up to 1:5 in some populations like Armenians.^[32] The risk of amyloidosis in untreated individuals varies by ethnicity, genotype, and other factors, ranging from approximately 10% to over 60% in certain populations such as those of Turkish origin.^[49]^[50] Inheritance follows an autosomal recessive pattern, requiring homozygous or compound heterozygous states for pathogenic MEFV variants to typically cause disease, though incomplete penetrance is observed in heterozygotes, leading to milder or atypical presentations in some carriers.^[5] Diagnosis relies on the Tel Hashomer criteria, which require at least one major criterion (recurrent fever ≥38°C with typical serositis attacks in the abdomen, chest, joints, or skin) or two minor criteria (incomplete attacks or favorable response to colchicine), often supported by features such as age of onset before 20 years, parental consanguinity, or ethnic background.^[51]

Other Pyrinopathies

Pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) is a rare autosomal dominant disorder caused by heterozygous mutations in exon 2 of the MEFV gene, such as p.E244K and p.S242R, which disrupt the 14-3-3 binding motif essential for pyrin autoinhibition.^[52] Clinically, PAAND manifests with prolonged episodes of fever lasting several weeks, severe neutrophilic dermatoses resembling pyoderma gangrenosum, arthralgias, myalgias, and elevated inflammatory markers, but notably lacks serositis or amyloidosis typical of other MEFV-related conditions.^[53] These features distinguish PAAND from more common recessive forms of MEFV-associated disease, with symptoms often emerging in childhood and showing variable response to colchicine.^[54] Pyrin-associated periodic fevers (PAPF), also termed atypical pyrin-associated autoinflammatory diseases, encompass dominant presentations linked to heterozygous variants in various MEFV exons, including p.M694del (exon 10), p.T577A (exon 8), p.H478Y (exon 5), and p.P373L (exon 3).^[53] Patients experience recurrent prolonged febrile attacks (1-6 days) accompanied by abdominal or chest pain, arthralgia, and elevated acute-phase reactants, often with late onset around age 18 years and without prominent serosal involvement.^[55] Inheritance is typically autosomal dominant, contrasting with recessive patterns in more prevalent MEFV disorders, and these conditions are rarer, with cases reported sporadically across diverse populations such as in Europe, Asia, and the Middle East, likely underestimated due to limited genetic screening.^[56] Emerging evidence suggests overlaps with Behçet's disease, where MEFV variants like p.M694V and p.M680I increase susceptibility to vascular and intestinal manifestations, potentially exacerbating autoinflammatory features through shared pyrin inflammasome dysregulation.^[57] Although no direct causal link establishes Behçet's as a primary pyrinopathy, these variants are enriched in affected cohorts, particularly those with refractory symptoms.^[58] Diagnosing these pyrinopathies poses challenges due to phenotypic overlap with other autoinflammatory syndromes, necessitating targeted next-generation sequencing of full MEFV exons rather than limited panels focused on common recessive variants.^[53] Variant-specific genotyping is crucial, as dominant mutations may not respond uniformly to standard therapies, and incomplete penetrance can delay recognition in families with mixed genotypes.^[55]

Clinical and Research Aspects

Genetic Testing and Diagnosis

Genetic testing for the MEFV gene is a cornerstone in diagnosing familial Mediterranean fever (FMF) and related pyrinopathies, typically involving molecular analysis to identify pathogenic variants. Targeted sequencing of specific exons, particularly exons 2 and 10, detects approximately 80% of disease-causing mutations in high-prevalence populations, as these regions harbor the majority of common variants such as p.Glu148Gln in exon 2 and p.Met694Val in exon 10.^[5] For broader evaluation, next-generation sequencing (NGS) panels that include MEFV alongside other autoinflammatory genes (e.g., NLRP3, TNFRSF1A, MVK) are increasingly utilized, enabling simultaneous assessment of monogenic periodic fever syndromes and improving diagnostic yield in atypical or overlapping cases.^[59] These approaches are recommended for symptomatic individuals meeting clinical criteria like recurrent fever and serositis, with sequence analysis achieving a 75-90% detection rate for biallelic pathogenic variants.^[5]^[60] Interpretation of MEFV variants follows the American College of Medical Genetics and Genomics (ACMG) guidelines, classifying them as pathogenic, likely pathogenic, uncertain significance, likely benign, or benign based on criteria such as population frequency, computational predictions, and functional evidence.^[61] Biallelic pathogenic variants (homozygous or compound heterozygous) strongly support an FMF diagnosis in symptomatic patients, while monoallelic findings require clinical correlation due to potential incomplete penetrance.^[5] Carrier screening is advised in high-risk ethnic groups, such as those of Armenian, Turkish, or North African descent, where carrier frequencies can reach 1:5-1:7; targeted testing for founder mutations like p.Met694Val is prioritized to inform reproductive counseling.^[5]^[60] The diagnostic utility of MEFV testing lies in confirming FMF in patients with compatible symptoms, guiding colchicine therapy initiation, and assessing prognosis through genotype-phenotype correlations. For instance, homozygosity for p.Met694Val is associated with earlier disease onset, more severe inflammatory attacks, and a sevenfold increased risk of amyloidosis compared to other genotypes, enabling risk stratification for renal monitoring.^[5]^[62] In up to 25% of FMF cases, only one pathogenic variant is identified, underscoring the need to integrate testing with clinical evaluation using criteria like the Tel Hashomer score.^[5] Limitations of MEFV testing include incomplete penetrance, where variant carriers may remain asymptomatic, complicating interpretation in low-penetrance scenarios or diverse ethnic backgrounds.^[5] Ethnic-specific variant panels are essential, as mutation spectra vary (e.g., higher p.Met694Val prevalence in Armenians versus p.Val726Ala in Jews), and standard panels may miss rare alleles outside targeted exons, leading to false negatives in 10-25% of cases.^[60] Variants of uncertain significance (VUS) further challenge diagnosis, often requiring family segregation studies or functional assays for reclassification per ACMG criteria.^[61] Despite these constraints, testing remains indispensable for precise diagnosis in clinical practice.^[5]

Therapeutic Approaches and Ongoing Research

The standard therapy for MEFV-related disorders, particularly familial Mediterranean fever (FMF), is daily colchicine prophylaxis at doses of 1-2 mg for adults, which reduces the frequency and severity of inflammatory attacks in approximately 60-95% of patients and prevents secondary amyloidosis in over 90% of adherent individuals.^[63]^[64] Colchicine exerts its effects by binding to tubulin and inhibiting microtubule polymerization, which disrupts inflammasome assembly and downstream IL-1β production.^[65] For the 5-10% of patients who are colchicine-resistant or intolerant—often those with homozygous M694V mutations—interleukin-1 (IL-1) inhibitors such as anakinra (100 mg daily subcutaneously) or canakinumab (150 mg every 4-8 weeks) provide effective alternatives, achieving attack-free periods in up to 80% of cases and reducing subclinical inflammation.^[66] Anti-TNF agents like etanercept may be considered for refractory articular manifestations, though evidence is more limited.^[67] Ongoing research focuses on personalized and novel interventions to address treatment gaps. Pharmacogenomic studies have identified polymorphisms in the ABCB1 gene, which encodes the P-glycoprotein transporter, as influencers of colchicine efficacy and required dosing; for instance, the C3435T variant correlates with response rates, with TT genotypes associated with better response to colchicine.^[68] Investigations into microbiome influences reveal gut dysbiosis in FMF patients, characterized by increased pro-inflammatory taxa like Enterobacter and Ruminococcus gnavus, which correlate with disease severity, genotype (e.g., biallelic mutations), and attack triggers, suggesting potential roles as environmental modifiers of MEFV penetrance.^[69]^[70] Emerging frontiers include gene-based therapies, with preclinical models using CRISPR/Cas9 to edit MEFV mutations in induced pluripotent stem cells (iPSCs) for studying pyrin function and IL-1β dysregulation, laying groundwork for potential editing strategies.^[71] Clinical trials are advancing biologics for amyloidosis prevention; for example, the KIN-ATTACK-FMF Phase III trial (NCT06336733, estimated start April 2024) evaluates on-demand anakinra versus standard care in colchicine-treated patients to reduce attack frequency, while real-world data support IL-6 inhibitors like tocilizumab in slowing amyloidosis progression in resistant cases.^[72]^[73] Recent analyses as of September 2025 highlight variations in global management practices for colchicine-resistant FMF, emphasizing the increasing use of biologics and the efficacy of tocilizumab in controlling attacks and inflammatory markers.^[74]^[75] These efforts aim to refine dosing via pharmacogenomics and explore microbiome modulation, such as probiotics, to enhance penetrance control.

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Jun 13, 2007 · Some results indicate a possible founder effect for the spatial scattering of MEFV's ... haplotype-sharing among ethnic groups. Genomics 1997; 44: ...
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Mutation and Haplotype Studies of Familial Mediterranean Fever ...
Among ∼200 anonymous Ashkenazi Jewish DNA samples, the MEFV carrier frequency was 21%, with E148Q the most common mutation. Several lines of evidence indicate ...
[35]
Familial Mediterranean Fever: Recent Developments in ... - NIH
Mar 23, 2017 · Until recently, it was a debate whether the disease-causing mutations in the MEFV gene were loss-of-function or gain-of-function mutations.
[36]
Gene–Dose Effect of MEFV Gain-of-Function Mutations Determines ...
Jun 10, 2020 · Spontaneous alteration of CD62L and CD11b expressions on neutrophils derived from MEFV mutation carriers and controls. Isolated neutrophils from ...
[37]
Pyrin dephosphorylation is sufficient to trigger inflammasome ... - NIH
M694V MEFV mutation, most frequently observed in FMF patient, triggers constitutive inflammasome activation only when combined to phospho‐null MEFV mutations.
[38]
Familial Mediterranean fever mutations lift the obligatory ... - PNAS
Nov 22, 2016 · (A) Schematic representation of different Flag-tagged Pyrin domain constructs. ... ; The International FMF Consortium, Ancient missense mutations ...<|control11|><|separator|>
[39]
Dysregulated production of interleukin-1β upon activation of the ...
Familial Mediterranean fever (FMF) is caused by mutations in pyrin, a protein expressed in innate immune cells that interacts with caspase-1 and other ...
[40]
Pathogenetic mechanisms of amyloid A amyloidosis - PNAS
Aug 19, 2013 · ... inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations. Rheumatology (Oxford) 45, 746–750 ...
[41]
Heightened endotoxin susceptibility of monocytes and neutrophils ...
Familial Mediterranean fever (FMF) is a relapsing autoinflammatory disorder, caused by various mutations in the MEFV gene, which encodes a protein called pyrin, ...Results · Monocytes Of Fmf Patients... · Cd11b Surface Expression And...
[42]
Accelerated Apoptosis of Neutrophils in Familial Mediterranean Fever
May 4, 2015 · The underlying cause of the disease is mutations in the MEFV gene, which encodes the protein called pyrin or marenostrin (1, 2). The protein is ...Apoptosis Rates In Pmn Cells · Induced Apoptotic Rates · Caspase-3 Mrna LevelMissing: impaired | Show results with:impaired
[43]
Factors triggering familial mediterranean fever attacks, do they ... - NIH
Mar 15, 2024 · Possible triggering factors include emotional stress, menstruation, and cold exposure. However, the number of studies in this area is limited.
[44]
Familial Mediterranean Fever - StatPearls - NCBI Bookshelf
Jul 31, 2023 · The gene responsible for FMF is the MEFV gene, which is located on the short arm of chromosome 16 (16 p13.3). MEFV gene encodes the 781 ...
[45]
https://www.pnas.org/doi/10.1073/pnas.1306621110
[46]
https://academic.oup.com/femspd/article/52/3/370/545715
[47]
A novel Pyrin-Associated Autoinflammation with Neutrophilic ... - NIH
Aug 23, 2017 · Here, we report a novel mutation in the MEFV gene in a family with clinical features of PAAND that results in an altered 14-3-3 binding motif ...
[48]
New Diseases Linked to MEFV Variants or Pyrinopathies
This review provides an update on AIDs associated with pathogenic variants in MEFV actually called pyrinopathies. Those include new dominant forms (exon 10 ...
[49]
Pyrin-associated autoinflammation with neutrophilic dermatosis
Jul 28, 2024 · Our findings highlight the importance of genetic evaluation of MEFV mutations in individuals with neutrophilic dermatosis and systemic symptoms.
[50]
A dominant pathogenic MEFV mutation causes atypical pyrin ... - NIH
Pyrin, a protein encoded by the MEFV gene, plays a vital role in innate immunity by sensing modifications in Rho GTPase and assembling the pyrin inflammasome, ...
[51]
A dominant pathogenic MEFV mutation causes atypical pyrin ...
Sep 7, 2023 · This mutation of pyrin 242 or 244 disrupts the ability of the inhibitory protein 14-3-3 to bind to pyrin, leading to direct activation of the ...
[52]
Possible Association of Mutations in the MEFV Gene with ... - PubMed
Apr 26, 2023 · Mutations in the MEFV gene may be associated with intestinal lesions of BD and refractoriness to treatment.
[53]
Association between MEFV Mutations M694V and M680I and ...
Several studies have identified an association between Behçet's disease (BD) and mutations in the Mediterranean fever (MEFV) gene, which was originally linked ...
[54]
AUTOG - Overview: Autoinflammatory Disorders Gene Panel, Varies
This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in 117 genes associated with autoinflammatory disorders.
[55]
Familial Mediterranean Fever (MEFV) Sequencing | Test Fact Sheet
May 14, 2025 · Variants outside the coding regions and intron-exon boundaries of targeted gene; Variants in the mitochondrial genome; Regulatory region and ...Missing: structure | Show results with:structure<|separator|>
[56]
standards_guidelines_for_the_in...
No information is available for this page. · Learn why
[57]
Familial Mediterranean Fever: Effects of Genotype and Ethnicity on ...
A significant association was found between amyloidosis and the most common mutation in exon 10 of the FMF gene (MEFV), M694V (for M694V homozygotes, relative ...Results · Amyloidosis · Effect Of Ethnicity On The...
[58]
EULAR recommendations for the management of familial ...
The aim of colchicine therapy is twofold in FMF: decreasing the frequency and severity of clinical attacks and preventing the risk of developing AA amyloidosis.
[59]
Prophylactic colchicine for familial Mediterranean fever - PubMed
Jun 5, 2025 · Complete response to colchicine is reported in 60-65% of patients with familial Mediterranean fever (FMF), partial response in 30-35%, and poor response in 5- ...Missing: pharmacogenomics | Show results with:pharmacogenomics
[60]
Colchicine --- update on mechanisms of action and therapeutic uses
The primary mechanism of action of colchicine is tubulin disruption. This leads to subsequent down regulation of multiple inflammatory pathways and modulation ...
[61]
IL-1 Inhibitors in the Treatment of Familial Mediterranean Fever - MDPI
Jun 7, 2024 · Colchicine has been the backbone of FMF treatment since the 1970s, owing to its preventive effects on attacks and secondary amyloidosis [5,6,7].
[62]
Update on the management of colchicine resistant Familial ...
Oct 15, 2019 · FMF patients who failed colchicine were successfully treated with anti IL-1, anti IL-6, or TNF inhibitors drugs. It is best to use colchicine in combination ...
[63]
ABCB1-Mediated Colchicine Transport and Its Implications in ... - MDPI
Colchicine's efficacy in FMF is well-established as it is used both to prevent acute attacks and reduce the risk of long-term complications. However, despite ...1. Introduction · 3. Results · 4. Discussion
[64]
Gut microbiota alterations are associated with phenotype and ...
Apr 2, 2024 · The gut microbiota of FMF patients correlates with disease characteristics and severity, with an increase in pro-inflammatory taxa in the most severe patients.
[65]
Gut Microbiota between Environment and Genetic Background in ...
Sep 3, 2020 · Growing evidences show a possible link between the microbiota and Familial Mediterranean Fever (FMF), through a shift of the relative abundance in microbial ...
[66]
Generation of iPSCs from a Patient with the M694V Mutation ... - MDPI
Furthermore, gene editing with CRISPR/Cas9 is used to understand the effect of the MEFV E583A mutation on IL-1β secretion [11].
[67]
Study Details | NCT06336733 - ClinicalTrials.gov
KIN-ATTACK-FMF will be the first randomized prospective study comparing the efficacy of on-demand anakinra versus standard of care treatment in patients with ...
[68]
Familial Mediterranean Fever; Recent Advances, Future Prospectives
Mar 23, 2025 · It was reported that approximately 25% of the clinically confirmed FMF patients did not have a biallelic mutation in the MEFV gene [17].