Materiały źródłowe

• #1 Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7672358/

  Familial Mediterranean fever (FMF) is caused by gain of function mutations of MEFV gene which encodes an immune regulatory protein, pyrin. […] Elucidation of some of the mechanisms underlying FMF pathogenesis has led to the discovery of critical immune pathways including intracellular danger sensors, inflammasomes, pyroptosis and NETosis, thereby transforming the understanding of mechanisms and treatment of prevalent inflammatory, metabolic, cardiovascular and degenerative diseases. […] Unusually for a disease largely inherited in an autosomal recessive fashion, FMF results from gain of function mutations of Mediterranean fever gene (MEFV), located on chromosome 16 (16p13.3). […] Upon activation, pyrin oligomerizes with other cellular proteins, forming a macromolecular complex called pyrin inflammasome that activates caspase-1 which, in turn, mediates the release of pro-inflammatory IL-1 and IL-18 from their inactive precursors and pyroptosis via the gasdermin D pathway.

• #2 Familial Mediterranean fever: overview of pathogenesis, clinical features and management – PubMed

  https://pubmed.ncbi.nlm.nih.gov/30938266/

  Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease, and is characterized by recurrent attacks of fever and polyserositis. It is associated with mutations in the MEFV gene encoding pyrin, which result in inflammasome activation and the uncontrolled production of IL-1. […] In Japanese patients with FMF, MEFV exon 10 mutations are associated with the more typical FMF phenotype. Conversely, Japanese FMF patients with mutations in MEFV exons 2 or 3 present with an atypical FMF phenotype. […] However, a minority of FMF patients are colchicine-resistant, and anti-IL-1 treatment has proven beneficial in suppressing inflammation in these patients.

• #3 Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7672358/

  Familial Mediterranean fever (FMF) is caused by gain of function mutations of MEFV gene which encodes an immune regulatory protein, pyrin. […] Elucidation of some of the mechanisms underlying FMF pathogenesis has led to the discovery of critical immune pathways including intracellular danger sensors, inflammasomes, pyroptosis and NETosis, thereby transforming the understanding of mechanisms and treatment of prevalent inflammatory, metabolic, cardiovascular and degenerative diseases. […] Unusually for a disease largely inherited in an autosomal recessive fashion, FMF results from gain of function mutations of Mediterranean fever gene (MEFV), located on chromosome 16 (16p13.3). […] Upon activation, pyrin oligomerizes with other cellular proteins, forming a macromolecular complex called pyrin inflammasome that activates caspase-1 which, in turn, mediates the release of pro-inflammatory IL-1 and IL-18 from their inactive precursors and pyroptosis via the gasdermin D pathway.

• #4 Familial Mediterranean Fever – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/hereditary-periodic-fever-syndromes/familial-mediterranean-fever

  Familial Mediterranean fever (FMF) is caused by mutations in the MEFV gene on the short arm of chromosome 16. The mutation is classically inherited in an autosomal recessive manner, but heterozygotes may manifest a clinical phenotype. FMF mutations are gain-of-function, that is, they confer new or enhanced activity on a protein, with a gene dosage effect (ie, more copies of the abnormal gene convey a greater effect). The MEFV gene normally codes a protein named pyrin, which is expressed in circulating neutrophils. […] Pyrin plays a role in innate immunity. It senses modifications in the activity of the small GTPase RhoA, a molecular switch that regulates a variety of signal transduction pathways including cytoskeletal organization. Pathogen virulence toxins (such as Clostridioides difficile, Burkholderia cenocepacia, and Vibrio cholera) downregulate RhoA activity and cause an assembly pyrin along with other proteins into a pyrin inflammasome, which eventually results in the production of the proinflammatory cytokine interleukin-1 beta (IL-1 beta). MEFV pathogenic variants favor the active state of pyrin and give rise to cell membrane rupture (pyroptosis) and the release of proinflammatory cytokines.

• #5 Familial Mediterranean Fever: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/330284-overview

  Nonsense or missense mutations in the MEFV (Mediterranean fever) gene appear to cause the disease in many cases. MEFV produces a protein called pyrin (because of the association with predominant fever); the protein is also called marenostrin (derived from the phrase „our sea,” because of the Mediterranean heritage of most patients). […] Pyrin is expressed mostly in neutrophils. To date, its main functions have been determined to involve the innate immune response, such as inflammasome assemblage and, as a part of the inflammasome, sensing intracellular danger signals, activating mediators of inflammation, and resolving inflammation by the autophagy of regulators of innate immunity. […] In patients with FMF, uninhibited pyrin activity results in uncontrolled production of interleukin-1 (IL-1), leading to episodes of inflammation (with accompanying fever) in the peritoneum, pleura, and joints; persistent subclinical inflammation is also common.

• #6 Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7672358/

  In FMF, mutations in MEFV gene impair interaction of pyrin with microtubules, PKN and 14-3-3 proteins facilitating formation of a proinflammatory pyrin inflammasome. […] Over activation of the pyrin inflammasome, and the resulting inflammation drives typical febrile inflammatory attacks observed in FMF. […] Pyrin has at least four functional domains; PYD, bBOX, CC and B30.2/SPRY. […] Cytoplasmic pyrin interacts with microtubules in cell skeleton and is a member of cytosolic pattern recognition receptors (PRRs) which are responsible for the initiation of rapid innate immune responses by sensing endogenous danger- or exogenous pathogen- associated molecular patterns (DAMPs and PAMPs). […] In physiologic conditions, RhoA GTPase activates the serine-threonine kinases; PKN1 and PKN2, that bind and phosphorylate pyrin.

• #7 Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7672358/

  In FMF, mutations in MEFV gene impair interaction of pyrin with microtubules, PKN and 14-3-3 proteins facilitating formation of a proinflammatory pyrin inflammasome. […] Over activation of the pyrin inflammasome, and the resulting inflammation drives typical febrile inflammatory attacks observed in FMF. […] Pyrin has at least four functional domains; PYD, bBOX, CC and B30.2/SPRY. […] Cytoplasmic pyrin interacts with microtubules in cell skeleton and is a member of cytosolic pattern recognition receptors (PRRs) which are responsible for the initiation of rapid innate immune responses by sensing endogenous danger- or exogenous pathogen- associated molecular patterns (DAMPs and PAMPs). […] In physiologic conditions, RhoA GTPase activates the serine-threonine kinases; PKN1 and PKN2, that bind and phosphorylate pyrin.

• #8 An Update on Familial Mediterranean Fever

  https://www.mdpi.com/1422-0067/24/11/9584

  Pyrin, the protein product of the MEFV gene, is an immunoregulatory molecule made up of 781 amino acids, interacting with the inflammasome components that can be activated in response to microbes. […] Most FMF causative mutations are found in the B30.2 domain. […] The distinctive structure of the PYD domain (amino acids 1–300), identified for the first time when the MEFV gene was cloned, was not analogous to any other protein domain known at the time; hence, it was named the PYD or PYRIN domain. […] Since its discovery, it has been found in more than 20 proteins regulating inflammation. […] It is responsible for the homotypic interaction with ASC, an apoptosis-associated speck-like protein that promotes the activation of caspase-1. […] Typically, ASC oligomerises with one of the NLRP proteins and with procaspase-1 through homotypic CARD (Caspase recruitment domain) interactions to make up the inflammasome.

• #9 An Update on Familial Mediterranean Fever

  https://www.mdpi.com/1422-0067/24/11/9584

  Pyrin, the protein product of the MEFV gene, is an immunoregulatory molecule made up of 781 amino acids, interacting with the inflammasome components that can be activated in response to microbes. […] Most FMF causative mutations are found in the B30.2 domain. […] The distinctive structure of the PYD domain (amino acids 1–300), identified for the first time when the MEFV gene was cloned, was not analogous to any other protein domain known at the time; hence, it was named the PYD or PYRIN domain. […] Since its discovery, it has been found in more than 20 proteins regulating inflammation. […] It is responsible for the homotypic interaction with ASC, an apoptosis-associated speck-like protein that promotes the activation of caspase-1. […] Typically, ASC oligomerises with one of the NLRP proteins and with procaspase-1 through homotypic CARD (Caspase recruitment domain) interactions to make up the inflammasome.

• #10 Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7672358/

  Phosphorylated pyrin binds to inhibitory 14-3-3 proteins and this process retains pyrin in an inactive state that prevents formation of the pyrin inflammasome. […] In FMF, mutations in MEFV gene impair interaction of pyrin with microtubules, PKN and 14-3-3 proteins facilitating formation of a proinflammatory pyrin inflammasome. […] The most common MEFV variant is M694V (c.2080AG) in FMF endemic areas. […] Most of the pathogenic/likely pathogenic variants are located on exon 10 which encodes B30.2/SPRY domain, responsible for the activation of caspase-1.

• #11 Familial Mediterranean Fever; Recent Advances, Future Prospectives

  https://www.mdpi.com/2075-4418/15/7/813

  Most of the common and severe MEFV mutations are clustered around the C terminal of the B30.2 domain, which is important for controlling pyrin phosphorylation by inhibiting the binding of PKN1, resulting in a lowered threshold for pyrin inflammasome activation. […] A recent study by Park et al. has reported the possible selective advantage of MEFV mutations, since their carrier frequencies are very high in several Mediterranean populations. […] In summary, FMF mutations in Mediterranean populations might lead to a positive selection against plague due to increased resistance to Y. pestis.

• #12 Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7672358/

  In FMF, mutations in MEFV gene impair interaction of pyrin with microtubules, PKN and 14-3-3 proteins facilitating formation of a proinflammatory pyrin inflammasome. […] Over activation of the pyrin inflammasome, and the resulting inflammation drives typical febrile inflammatory attacks observed in FMF. […] Pyrin has at least four functional domains; PYD, bBOX, CC and B30.2/SPRY. […] Cytoplasmic pyrin interacts with microtubules in cell skeleton and is a member of cytosolic pattern recognition receptors (PRRs) which are responsible for the initiation of rapid innate immune responses by sensing endogenous danger- or exogenous pathogen- associated molecular patterns (DAMPs and PAMPs). […] In physiologic conditions, RhoA GTPase activates the serine-threonine kinases; PKN1 and PKN2, that bind and phosphorylate pyrin.

• #13 Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7672358/

  Phosphorylated pyrin binds to inhibitory 14-3-3 proteins and this process retains pyrin in an inactive state that prevents formation of the pyrin inflammasome. […] In FMF, mutations in MEFV gene impair interaction of pyrin with microtubules, PKN and 14-3-3 proteins facilitating formation of a proinflammatory pyrin inflammasome. […] The most common MEFV variant is M694V (c.2080AG) in FMF endemic areas. […] Most of the pathogenic/likely pathogenic variants are located on exon 10 which encodes B30.2/SPRY domain, responsible for the activation of caspase-1.

• #14 Familial Mediterranean fever – Wikipedia

  https://en.wikipedia.org/wiki/Familial_Mediterranean_fever

  In its basal state, pyrin is kept inactive by a chaperone protein (belonging to the family of 14.3.3 proteins) linked to pyrin through phosphorylated serine residues. The dephosphorylation of pyrin is an essential prerequisite for the activation of the pyrin inflammasome. Inactivation of RhoA GTPases (by bacterial toxins, for example) leads to the inactivation of PKN1 / PKN2 kinases and dephosphorylation of pyrin. In healthy subjects, the dephosphorylation step alone does not cause activation of the pyrin inflammasome. In contrast, in FMF patients, the dephosphorylation of serines is sufficient to trigger the activation of the pyrin inflammasome. This suggests that there is a two-level regulation and that the second regulatory mechanism (independent of (de)phosphorylation) is deficient in FMF patients. This deficient mechanism is probably located at the level of the B30.2 domain (exon 10) where most of the pathogenic mutations associated with FMF are located. It is probably the interaction of this domain with the cytoskeleton (microtubules) that is failing, as suggested by the efficacy of colchicine.

• #15 Familial Mediterranean fever – Wikipedia

  https://en.wikipedia.org/wiki/Familial_Mediterranean_fever

  In its basal state, pyrin is kept inactive by a chaperone protein (belonging to the family of 14.3.3 proteins) linked to pyrin through phosphorylated serine residues. The dephosphorylation of pyrin is an essential prerequisite for the activation of the pyrin inflammasome. Inactivation of RhoA GTPases (by bacterial toxins, for example) leads to the inactivation of PKN1 / PKN2 kinases and dephosphorylation of pyrin. In healthy subjects, the dephosphorylation step alone does not cause activation of the pyrin inflammasome. In contrast, in FMF patients, the dephosphorylation of serines is sufficient to trigger the activation of the pyrin inflammasome. This suggests that there is a two-level regulation and that the second regulatory mechanism (independent of (de)phosphorylation) is deficient in FMF patients. This deficient mechanism is probably located at the level of the B30.2 domain (exon 10) where most of the pathogenic mutations associated with FMF are located. It is probably the interaction of this domain with the cytoskeleton (microtubules) that is failing, as suggested by the efficacy of colchicine.

• #16 An Update on Familial Mediterranean Fever

  https://www.mdpi.com/1422-0067/24/11/9584

  FMF-associated mutations of the B30.2 domain make the protein less prone to phosphorylation, thus leading to constitutive activation of the pyrin inflammasome, influencing the interaction between the regulatory protein 14-3-3 and pyrin. […] Homozygous pyrin “knockin” mice harbouring mutant human B30.2 domains, but not pyrin-deficient, exhibited spontaneous inflammation similar to but more severe than human FMF. […] These pivotal studies provide the final evidence for an ASC-dependent, NLRP3-independent inflammasome in which gain-of-function pyrin mutations cause FMF. […] The clinical consequence of the dosage effect of MEFV variants was described in children with periodic fevers, in which the prevalence of FMF-related clinical manifestations was significantly correlated to the number and pathogenicity of MEFV variants carried by the patients.

• #17 Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7672358/

  In FMF, mutations in MEFV gene impair interaction of pyrin with microtubules, PKN and 14-3-3 proteins facilitating formation of a proinflammatory pyrin inflammasome. […] Over activation of the pyrin inflammasome, and the resulting inflammation drives typical febrile inflammatory attacks observed in FMF. […] Pyrin has at least four functional domains; PYD, bBOX, CC and B30.2/SPRY. […] Cytoplasmic pyrin interacts with microtubules in cell skeleton and is a member of cytosolic pattern recognition receptors (PRRs) which are responsible for the initiation of rapid innate immune responses by sensing endogenous danger- or exogenous pathogen- associated molecular patterns (DAMPs and PAMPs). […] In physiologic conditions, RhoA GTPase activates the serine-threonine kinases; PKN1 and PKN2, that bind and phosphorylate pyrin.

• #18 Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7672358/

  Phosphorylated pyrin binds to inhibitory 14-3-3 proteins and this process retains pyrin in an inactive state that prevents formation of the pyrin inflammasome. […] In FMF, mutations in MEFV gene impair interaction of pyrin with microtubules, PKN and 14-3-3 proteins facilitating formation of a proinflammatory pyrin inflammasome. […] The most common MEFV variant is M694V (c.2080AG) in FMF endemic areas. […] Most of the pathogenic/likely pathogenic variants are located on exon 10 which encodes B30.2/SPRY domain, responsible for the activation of caspase-1.

• #19 Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7672358/

  Familial Mediterranean fever (FMF) is caused by gain of function mutations of MEFV gene which encodes an immune regulatory protein, pyrin. […] Elucidation of some of the mechanisms underlying FMF pathogenesis has led to the discovery of critical immune pathways including intracellular danger sensors, inflammasomes, pyroptosis and NETosis, thereby transforming the understanding of mechanisms and treatment of prevalent inflammatory, metabolic, cardiovascular and degenerative diseases. […] Unusually for a disease largely inherited in an autosomal recessive fashion, FMF results from gain of function mutations of Mediterranean fever gene (MEFV), located on chromosome 16 (16p13.3). […] Upon activation, pyrin oligomerizes with other cellular proteins, forming a macromolecular complex called pyrin inflammasome that activates caspase-1 which, in turn, mediates the release of pro-inflammatory IL-1 and IL-18 from their inactive precursors and pyroptosis via the gasdermin D pathway.

• #20 An Update on Familial Mediterranean Fever

  https://www.mdpi.com/1422-0067/24/11/9584

  This complex brings two molecules of precursor pro-caspase-1 into close proximity, leading to autocatalysis and, therefore, the release of the active catalytic p20 and p10 domains of caspase-1. […] Caspase-1, in turn, cleaves the pro-form of IL-1β into its active form. […] The process of pyrin inflammasome inhibition has been described to depend on RhoA phosphorylation. […] RhoA activates the serine–threonine kinases PKN1 and PKN2 that phosphorylate pyrin. […] Phosphorylated pyrin binds to regulatory proteins, such as 14-3-3, that avoid the formation of the pyrin inflammasome. […] The toxins produced by bacteria are able to inactivate RhoA and, in turn, inhibit PKN1 and PKN2 activation, with the consequent dephosphorylation of pyrin. […] Pyrin is, therefore, able to interact with ASC and caspase-1, forming the pyrin inflammasome, with the consequent cleavage and secretion of IL-1β.

• #21 Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7672358/

  In FMF, mutations in MEFV gene impair interaction of pyrin with microtubules, PKN and 14-3-3 proteins facilitating formation of a proinflammatory pyrin inflammasome. […] Over activation of the pyrin inflammasome, and the resulting inflammation drives typical febrile inflammatory attacks observed in FMF. […] Pyrin has at least four functional domains; PYD, bBOX, CC and B30.2/SPRY. […] Cytoplasmic pyrin interacts with microtubules in cell skeleton and is a member of cytosolic pattern recognition receptors (PRRs) which are responsible for the initiation of rapid innate immune responses by sensing endogenous danger- or exogenous pathogen- associated molecular patterns (DAMPs and PAMPs). […] In physiologic conditions, RhoA GTPase activates the serine-threonine kinases; PKN1 and PKN2, that bind and phosphorylate pyrin.

• #22 Familial Mediterranean Fever; Recent Advances, Future Prospectives

  https://www.mdpi.com/2075-4418/15/7/813

  Familial Mediterranean Fever (FMF) is inherited with autosomal recessive mutations on the MEFV gene, which encodes the pyrin protein. Pyrin is a fundamental element of the NLRP3 inflammasome complex. Mutation of this protein initiates caspase-1 activation and IL-1b production, causing excessive inflammation. […] Mutations in the MEFV gene cause IL-1b overproduction, which in turn results in excessive inflammation. […] Chae et al. have shown in MEFV knock-in mice models that gain-of-function mutations of pyrin protein led to overproduction of IL-1b via associated speck-like protein-containing CARD (ASC) and caspase-1 activation. […] There is a control mechanism for pyrin inflammasome in healthy individuals. RhoA-activated serine-threonine kinases (PKN1 and PKN 2) bind and phosphorylate pyrin, which binds to regulatory 14-3-3 proteins, inhibiting pyrin inflammasome.

• #23 Updates on the role of epigenetics in familial mediterranean fever (FMF) | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-024-03098-w

  The NLRP3 inflammasome was also found to be significantly demethylated in monocytes derived from FMF patients and associated with increased expression of IL-1. […] There is a growing body of evidence indicating that FMF is not a simple monogenic disease and that epigenetics play an important role in the manifestation of this disease.

• #24 Frontiers | Familial Mediterranean Fever: Recent Developments in Pathogenesis and New Recommendations for Management

  https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.00253/full

  Familial Mediterranean fever (FMF) is caused by mutations in the MEFV gene coding for pyrin, which is a component of inflammasome functioning in inflammatory response and production of interleukin-1β (IL-1β). […] Recent studies have shown that pyrin recognizes bacterial modifications in Rho GTPases, which results in inflammasome activation and increase in IL-1β. […] Pyrin, encoded by MEFV, has been suggested to interact with ASC (the inflammasome adaptor protein). The subsequent assembly of the inflammasome was suggested to activate caspase-1 leading to the cleavage and activation of IL-1β. […] Until recently, it was a debate whether the disease-causing mutations in the MEFV gene were loss-of-function or gain-of-function mutations. […] Supporting the loss-of-function model, Papin et al. demonstrated an increase in caspase-1 activation and IL-1β secretion as a result of pyrin knockdown.

• #25 Frontiers | Familial Mediterranean Fever: Recent Developments in Pathogenesis and New Recommendations for Management

  https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.00253/full

  On the other hand, in compliance with the gain-of-function model, Booty et al. demonstrated a significant increase in pyrin expression in FMF patients compared to healthy controls. […] These data confirmed that the mutations associated with FMF were gain-of-function mutations and suggested that FMF was a pyrin inflammasomopathy. […] The detection of pathogenic microorganisms by PRRs triggers the formation of inflammasome. Recent data suggest that pyrin is also a PRR. […] Recent studies have also shown that TcdB could trigger caspase-1 activation and IL-1β production; thus, it can activate the inflammasome. […] These results suggest that the bacterial toxins modifying RHO could trigger caspase-1 activation and IL-1β production; thus induce the inflammasome. […] The inflammasome activation by these toxins (TcdB, C3, and T6SS) was independent of NLRP3 and NLRC4 but was decreased in ASC−/− and MEFV−/− bone marrow-derived macrophages.

• #26 Frontiers | Familial Mediterranean Fever: Recent Developments in Pathogenesis and New Recommendations for Management

  https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.00253/full

  These results also support the “gain-of-function” model in the pathogenesis of FMF. […] Pyrin is activated when dephosphorylated at Ser208/Ser242. The binding of PKN1 to pyrin is decreased with the B30.2 domain where most of the common and severe MEFV mutations are clustered. […] These data enlighten the effect of mutations on pyrin function and the downstream event of RhoA inhibiting pyrin.

• #27 Familial Mediterranean Fever; Recent Advances, Future Prospectives

  https://www.mdpi.com/2075-4418/15/7/813

  Familial Mediterranean Fever (FMF) is inherited with autosomal recessive mutations on the MEFV gene, which encodes the pyrin protein. Pyrin is a fundamental element of the NLRP3 inflammasome complex. Mutation of this protein initiates caspase-1 activation and IL-1b production, causing excessive inflammation. […] Mutations in the MEFV gene cause IL-1b overproduction, which in turn results in excessive inflammation. […] Chae et al. have shown in MEFV knock-in mice models that gain-of-function mutations of pyrin protein led to overproduction of IL-1b via associated speck-like protein-containing CARD (ASC) and caspase-1 activation. […] There is a control mechanism for pyrin inflammasome in healthy individuals. RhoA-activated serine-threonine kinases (PKN1 and PKN 2) bind and phosphorylate pyrin, which binds to regulatory 14-3-3 proteins, inhibiting pyrin inflammasome.

• #28 Frontiers | Familial Mediterranean Fever: Recent Developments in Pathogenesis and New Recommendations for Management

  https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.00253/full

  On the other hand, in compliance with the gain-of-function model, Booty et al. demonstrated a significant increase in pyrin expression in FMF patients compared to healthy controls. […] These data confirmed that the mutations associated with FMF were gain-of-function mutations and suggested that FMF was a pyrin inflammasomopathy. […] The detection of pathogenic microorganisms by PRRs triggers the formation of inflammasome. Recent data suggest that pyrin is also a PRR. […] Recent studies have also shown that TcdB could trigger caspase-1 activation and IL-1β production; thus, it can activate the inflammasome. […] These results suggest that the bacterial toxins modifying RHO could trigger caspase-1 activation and IL-1β production; thus induce the inflammasome. […] The inflammasome activation by these toxins (TcdB, C3, and T6SS) was independent of NLRP3 and NLRC4 but was decreased in ASC−/− and MEFV−/− bone marrow-derived macrophages.

• #29 Familial Mediterranean Fever – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/hereditary-periodic-fever-syndromes/familial-mediterranean-fever

  Familial Mediterranean fever (FMF) is caused by mutations in the MEFV gene on the short arm of chromosome 16. The mutation is classically inherited in an autosomal recessive manner, but heterozygotes may manifest a clinical phenotype. FMF mutations are gain-of-function, that is, they confer new or enhanced activity on a protein, with a gene dosage effect (ie, more copies of the abnormal gene convey a greater effect). The MEFV gene normally codes a protein named pyrin, which is expressed in circulating neutrophils. […] Pyrin plays a role in innate immunity. It senses modifications in the activity of the small GTPase RhoA, a molecular switch that regulates a variety of signal transduction pathways including cytoskeletal organization. Pathogen virulence toxins (such as Clostridioides difficile, Burkholderia cenocepacia, and Vibrio cholera) downregulate RhoA activity and cause an assembly pyrin along with other proteins into a pyrin inflammasome, which eventually results in the production of the proinflammatory cytokine interleukin-1 beta (IL-1 beta). MEFV pathogenic variants favor the active state of pyrin and give rise to cell membrane rupture (pyroptosis) and the release of proinflammatory cytokines.

• #30 Familial Mediterranean fever – Wikipedia

  https://en.wikipedia.org/wiki/Familial_Mediterranean_fever

  Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by mutations in the Mediterranean fever (MEFV) gene, which encodes a 781-amino acid protein called pyrin. […] Virtually all cases are due to a mutation in the Mediterranean Fever (MEFV) gene on the chromosome 16, which codes for a protein called pyrin or marenostrin. Various mutations of this gene lead to FMF, although some mutations cause a more severe picture than others. Mutations occur mainly in exons 2, 3, 5 and 10. […] The function of pyrin is not fully known, but in short, it is a protein that binds to the adaptor ASC and the proform of the enzyme caspase-1 to generate multiprotein complexes called inflammasomes in response to certain infections. In healthy individuals, pyrin-mediated inflammasome assembly (which leads to the caspase 1) dependent processing and secretion of the pro-inflammatory cytokines (such as interleukin-18 (IL-18) and IL-1) is a response to enterotoxins from certain bacteria. The gain-of-function mutations in the MEFV gene cause pyrin to be more active in the body, which increases inflammasome formation.

• #31 Frontiers | Familial Mediterranean Fever: Recent Developments in Pathogenesis and New Recommendations for Management

  https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.00253/full

  Familial Mediterranean fever (FMF) is caused by mutations in the MEFV gene coding for pyrin, which is a component of inflammasome functioning in inflammatory response and production of interleukin-1β (IL-1β). […] Recent studies have shown that pyrin recognizes bacterial modifications in Rho GTPases, which results in inflammasome activation and increase in IL-1β. […] Pyrin, encoded by MEFV, has been suggested to interact with ASC (the inflammasome adaptor protein). The subsequent assembly of the inflammasome was suggested to activate caspase-1 leading to the cleavage and activation of IL-1β. […] Until recently, it was a debate whether the disease-causing mutations in the MEFV gene were loss-of-function or gain-of-function mutations. […] Supporting the loss-of-function model, Papin et al. demonstrated an increase in caspase-1 activation and IL-1β secretion as a result of pyrin knockdown.

• #32 Familial Mediterranean Fever – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/hereditary-periodic-fever-syndromes/familial-mediterranean-fever

  Familial Mediterranean fever (FMF) is caused by mutations in the MEFV gene on the short arm of chromosome 16. The mutation is classically inherited in an autosomal recessive manner, but heterozygotes may manifest a clinical phenotype. FMF mutations are gain-of-function, that is, they confer new or enhanced activity on a protein, with a gene dosage effect (ie, more copies of the abnormal gene convey a greater effect). The MEFV gene normally codes a protein named pyrin, which is expressed in circulating neutrophils. […] Pyrin plays a role in innate immunity. It senses modifications in the activity of the small GTPase RhoA, a molecular switch that regulates a variety of signal transduction pathways including cytoskeletal organization. Pathogen virulence toxins (such as Clostridioides difficile, Burkholderia cenocepacia, and Vibrio cholera) downregulate RhoA activity and cause an assembly pyrin along with other proteins into a pyrin inflammasome, which eventually results in the production of the proinflammatory cytokine interleukin-1 beta (IL-1 beta). MEFV pathogenic variants favor the active state of pyrin and give rise to cell membrane rupture (pyroptosis) and the release of proinflammatory cytokines.

• #33 Frontiers | Familial Mediterranean Fever: Recent Developments in Pathogenesis and New Recommendations for Management

  https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.00253/full

  On the other hand, in compliance with the gain-of-function model, Booty et al. demonstrated a significant increase in pyrin expression in FMF patients compared to healthy controls. […] These data confirmed that the mutations associated with FMF were gain-of-function mutations and suggested that FMF was a pyrin inflammasomopathy. […] The detection of pathogenic microorganisms by PRRs triggers the formation of inflammasome. Recent data suggest that pyrin is also a PRR. […] Recent studies have also shown that TcdB could trigger caspase-1 activation and IL-1β production; thus, it can activate the inflammasome. […] These results suggest that the bacterial toxins modifying RHO could trigger caspase-1 activation and IL-1β production; thus induce the inflammasome. […] The inflammasome activation by these toxins (TcdB, C3, and T6SS) was independent of NLRP3 and NLRC4 but was decreased in ASC−/− and MEFV−/− bone marrow-derived macrophages.

• #34 Familial Mediterranean Fever – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/hereditary-periodic-fever-syndromes/familial-mediterranean-fever

  There is strong evidence that Yersinia pestis, the cause of bubonic plague, led to the positive selection of FMF-associated MEFV mutations. These mutations confer a survival advantage to certain people who harbor Yersinia pestis. […] Diagnosis of familial Mediterranean fever is mainly clinical based on Tel HaShomer criteria, but genetic testing is available and is particularly useful in evaluation of atypical cases. However, current genetic testing is not infallible; some patients with phenotypically unmistakeable FMF have only a single mutated gene or occasionally no evident mutations in the MEFV gene. About 10 to 20% of patients who meet the diagnostic criteria for FMF do not have MEFV mutations, which suggests epigenetic and environmental factors contribute to the disease pathogenesis.

• #35 An Update on Familial Mediterranean Fever

  https://www.mdpi.com/1422-0067/24/11/9584

  Dependence from RhoA makes the pyrin inflammasome distinct from other inflammasomes that are activated by pattern-recognition receptors: it does not directly interact with PAMPs and DAMPs. […] The crucial role of the pyrin inflammasome in the response to pathogens inducing toxin release (such as Y. pestis) led to the fascinating hypothesis of a possible selective advantage for individual carriers of MEFV causative during plague times. […] In fact, the Yersinia pestis virulence factor, called YopM, stimulates the PKN-1/2-mediated phosphorylation of pyrin and thereby the inhibition of pyrin inflammasome reducing IL-1β secretion in response to infection. […] In turn, MEFV pathogenic variants attenuate the pyrin–YopM interaction, thus interfering with the YopM-induced interleukin-1β suppression.

• #36 Familial Mediterranean Fever; Recent Advances, Future Prospectives

  https://www.mdpi.com/2075-4418/15/7/813

  Most of the common and severe MEFV mutations are clustered around the C terminal of the B30.2 domain, which is important for controlling pyrin phosphorylation by inhibiting the binding of PKN1, resulting in a lowered threshold for pyrin inflammasome activation. […] A recent study by Park et al. has reported the possible selective advantage of MEFV mutations, since their carrier frequencies are very high in several Mediterranean populations. […] In summary, FMF mutations in Mediterranean populations might lead to a positive selection against plague due to increased resistance to Y. pestis.

• #37 Immunologic Aspects of Plague Immunity and Familial Mediterranean Fever

  https://www.heraldopenaccess.us/openaccess/immunologic-aspects-of-plague-immunity-and-familial-mediterranean-fever

  Using a Trojan-horse type of strategy, Yersinia pestis enters host cells through a prototypical type III secretion system used by other gram-negative rod bacteria. It has a broad range of sophisticated mechanisms to inactivate the body’s immune system and quickly disseminate throughout the body. It has several Yops (Yersinia outer proteins) which wreak havoc on the invaded host. YopM inhibits caspase-1 and blocks the pyrin inflammasome. Yersinia pestis reduces production of IL-1 and IL-18, blocking the immune system from mounting a robust immune response. The bacteria shut off natural immune defenses and thus can overwhelm its human host easily, leading to death. […] Patients who carry the FMF mutation have a gain-of-function in the pyrin gene. Pyrin’s activity is always on. For infected subjects who lack the FMF mutation, Yersinia pestis shuts off pyrin. Molecular studies using pyrin knock-out mice demonstrate that lacking pyrin increases susceptibility to the plague infection, while having a superabundance of pyrin (which FMF mutation carriers have) dramatically increases resistance to the plague. The mutation confers natural resistance or immunity to the plague, enabling higher survival rates. Similar to carrying the sickle cell trait and having resistance to malaria, those harboring the FMF mutation are resistant to contracting the plague.

• #38 An Update on Familial Mediterranean Fever

  https://www.mdpi.com/1422-0067/24/11/9584

  Dependence from RhoA makes the pyrin inflammasome distinct from other inflammasomes that are activated by pattern-recognition receptors: it does not directly interact with PAMPs and DAMPs. […] The crucial role of the pyrin inflammasome in the response to pathogens inducing toxin release (such as Y. pestis) led to the fascinating hypothesis of a possible selective advantage for individual carriers of MEFV causative during plague times. […] In fact, the Yersinia pestis virulence factor, called YopM, stimulates the PKN-1/2-mediated phosphorylation of pyrin and thereby the inhibition of pyrin inflammasome reducing IL-1β secretion in response to infection. […] In turn, MEFV pathogenic variants attenuate the pyrin–YopM interaction, thus interfering with the YopM-induced interleukin-1β suppression.

• #39 Updates on the role of epigenetics in familial mediterranean fever (FMF) | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-024-03098-w

  Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease caused by mutations in the MEFV (Mediterranean Fever) gene that affects people originating from the Mediterranean Sea. The high variability in severity and clinical manifestations observed not only between ethnic groups but also between and within families is mainly related to MEFV allelic heterogeneity and to some modifying genes. […] In addition to the genetic factors underlying FMF, the environment plays a significant role in the development and manifestation of this disease through various epigenetic mechanisms, including DNA methylation, histone modification, and noncoding RNAs. Indeed, epigenetic events have been identified as an important pathophysiological determinant of FMF and co-factors shaping the clinical picture and outcome of the disease.

• #40 Updates on the role of epigenetics in familial mediterranean fever (FMF) | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-024-03098-w

  The clinical variability of the disease is mainly related to the allelic heterogeneity of the MEFV gene, with M694V exhibiting the highest penetrance and being associated with the most severe phenotype of the disease. […] Interestingly, numerous studies have recently shown that along with genetic susceptibility, epigenetic events are important pathophysiological factors contributing to the clinical manifestations of this disease in patients. […] The MEFV gene has a 998-base pair (bp) CpG island that covers a part of the first intron and the entire exon 2 of the gene. In this respect, it is expected that methylation of the MEFV gene might lead to phenotypic variability, and patients with a methylated variant of MEFV exon 2 may exhibit a more severe form of FMF. […] Given the involvement of pyrin in the inflammasome complex and the established connection between the NLRP13 inflammasome and the MEFV gene, researchers were intrigued to compare NLRP13 gene expression and methylation between FMF patients in crisis and healthy controls.

• #41 Updates on the role of epigenetics in familial mediterranean fever (FMF) | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-024-03098-w

  The NLRP3 inflammasome was also found to be significantly demethylated in monocytes derived from FMF patients and associated with increased expression of IL-1. […] There is a growing body of evidence indicating that FMF is not a simple monogenic disease and that epigenetics play an important role in the manifestation of this disease.

• #42 Assessment of Circulating Microribonucleic Acids in Patients With Familial Mediterranean Fever | Volume 35 – Issue 1 – March 2020 | Archives of Rheumatology

  https://www.archivesofrheumatology.org/full-text/1077

  Objectives: This study aims to evaluate the plasma expression of microribonucleic acids (miRNAs) that may be associated with the pathogenesis of familial Mediterranean fever (FMF). […] Our findings showed significant alterations in the plasma expression of miRNA-155 and miRNA-204 in FMF patients compared to HCs. Our data suggest that miRNA-155 and miRNA-204 may be related to the pathogenesis of FMF. Further comprehensive and functional researches may help to clarify the role of miRNAs in FMF and elucidate the pathogenesis of the disease. […] The impacts of miRNA-155 in the physiological function of the immune system have also been shown. […] Moreover, the miRNA-204 was demonstrated to have suppressor effects on inflammatory cytokine production by targeting the phosphoinositide 3-kinase gamma (PI3K) pathway and that plasma miR-204 level can be used as a potential biomarker in patients with FMF.

• #43 Assessment of Circulating Microribonucleic Acids in Patients With Familial Mediterranean Fever | Volume 35 – Issue 1 – March 2020 | Archives of Rheumatology

  https://www.archivesofrheumatology.org/full-text/1077

  Objectives: This study aims to evaluate the plasma expression of microribonucleic acids (miRNAs) that may be associated with the pathogenesis of familial Mediterranean fever (FMF). […] Our findings showed significant alterations in the plasma expression of miRNA-155 and miRNA-204 in FMF patients compared to HCs. Our data suggest that miRNA-155 and miRNA-204 may be related to the pathogenesis of FMF. Further comprehensive and functional researches may help to clarify the role of miRNAs in FMF and elucidate the pathogenesis of the disease. […] The impacts of miRNA-155 in the physiological function of the immune system have also been shown. […] Moreover, the miRNA-204 was demonstrated to have suppressor effects on inflammatory cytokine production by targeting the phosphoinositide 3-kinase gamma (PI3K) pathway and that plasma miR-204 level can be used as a potential biomarker in patients with FMF.

• #44 Assessment of Circulating Microribonucleic Acids in Patients With Familial Mediterranean Fever | Volume 35 – Issue 1 – March 2020 | Archives of Rheumatology

  https://www.archivesofrheumatology.org/full-text/1077

  In a study about the relationship between genotype and plasma miRNA expressions in patients with FMF, it has been shown that the plasma mRNA-452 expressions were increased in M694V (+) patients (more pronounced in homozygous ones) and associated with worse clinical course. […] Our findings suggest that miRNA-155 may be involved in the pathogenesis of FMF with a negative regulatory effect through targeting SOCS1, and that the reduction of plasma levels may be related to disease exacerbation. […] Our results showed that the plasma miRNA-155 and miRNA-204 levels are significantly decreased in patients with FMF and it was thought that these molecules may have roles in the pathogenesis of FMF. Increased plasma levels of miRNA-16 and miRNA-451 in FMF patients also suggest that these molecules may be associated with disease pathogenesis.

• #45 Investigating The Role Of IL-22 In The Pathogenesis Of Familial Mediterranean FEVER – ACR Meeting Abstracts

  https://acrabstracts.org/abstract/investigating-the-role-of-il-22-in-the-pathogenesis-of-familial-mediterranean-fever/

  Familial mediterranean fever (FMF) is a familial disease characterized by recurrent episodes of febrile serositis, peritonitis, arthritis and pleuritis. […] During the acute attacks, neutrophil accumulation, elevations in acute phase reactant levels, several non-specific immunological abnormalities and increased several proinflammatory cytokines, such as IL-1, IL-8, IL-6 and TNF-alpha have been described. […] IL-22 acts synergistically with TNF alpha, IL-1 beta or IL-17 and induces acute phase reactants. […] These findings indicate that IL-22 represents a novel type of immune mediator that is produced by immune cells which regulates tissue protection and homeostasis. […] The high levels of serum IL-22, in active and inactive patients with FMF suggest that IL-22 may play a significant role of in the pathogenesis of FMF.

• #46 Investigating The Role Of IL-22 In The Pathogenesis Of Familial Mediterranean FEVER – ACR Meeting Abstracts

  https://acrabstracts.org/abstract/investigating-the-role-of-il-22-in-the-pathogenesis-of-familial-mediterranean-fever/

  Familial mediterranean fever (FMF) is a familial disease characterized by recurrent episodes of febrile serositis, peritonitis, arthritis and pleuritis. […] During the acute attacks, neutrophil accumulation, elevations in acute phase reactant levels, several non-specific immunological abnormalities and increased several proinflammatory cytokines, such as IL-1, IL-8, IL-6 and TNF-alpha have been described. […] IL-22 acts synergistically with TNF alpha, IL-1 beta or IL-17 and induces acute phase reactants. […] These findings indicate that IL-22 represents a novel type of immune mediator that is produced by immune cells which regulates tissue protection and homeostasis. […] The high levels of serum IL-22, in active and inactive patients with FMF suggest that IL-22 may play a significant role of in the pathogenesis of FMF.

• #47 Familial Mediterranean Fever: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/330284-overview

  FMF attacks are also characterized by the release of neutrophil extracellular traps (NET), which are chromatin laments decorated with neutrophil granular and cytoplasmic proteins, including active IL-1. NETs restrict their own generation by a negative feedback mechanism, which may help explain the self-limited nature of FMF attacks. […] Presumably, the inflammatory episodes in persons with FMF lead to the excess production of amyloid A protein in the acute phase and reactant serum amyloid A with subsequent deposition in the kidneys. However, only patients with specific MEFV haplotypes develop amyloidosis.

• #48 Familial Mediterranean Fever: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/330284-overview

  FMF attacks are also characterized by the release of neutrophil extracellular traps (NET), which are chromatin laments decorated with neutrophil granular and cytoplasmic proteins, including active IL-1. NETs restrict their own generation by a negative feedback mechanism, which may help explain the self-limited nature of FMF attacks. […] Presumably, the inflammatory episodes in persons with FMF lead to the excess production of amyloid A protein in the acute phase and reactant serum amyloid A with subsequent deposition in the kidneys. However, only patients with specific MEFV haplotypes develop amyloidosis.

• #49 Updates on the role of epigenetics in familial mediterranean fever (FMF) | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-024-03098-w

  The clinical variability of the disease is mainly related to the allelic heterogeneity of the MEFV gene, with M694V exhibiting the highest penetrance and being associated with the most severe phenotype of the disease. […] Interestingly, numerous studies have recently shown that along with genetic susceptibility, epigenetic events are important pathophysiological factors contributing to the clinical manifestations of this disease in patients. […] The MEFV gene has a 998-base pair (bp) CpG island that covers a part of the first intron and the entire exon 2 of the gene. In this respect, it is expected that methylation of the MEFV gene might lead to phenotypic variability, and patients with a methylated variant of MEFV exon 2 may exhibit a more severe form of FMF. […] Given the involvement of pyrin in the inflammasome complex and the established connection between the NLRP13 inflammasome and the MEFV gene, researchers were intrigued to compare NLRP13 gene expression and methylation between FMF patients in crisis and healthy controls.

• #50 Familial Mediterranean fever – Wikipedia

  https://en.wikipedia.org/wiki/Familial_Mediterranean_fever

  It is not conclusively known what exactly sets off the attacks or why overproduction of IL-1 would lead to particular symptoms in particular organs, such as joints or the peritoneal cavity. However, steroid hormone catabolites (pregnanolone and etiocholanolone) have been shown to activate the pyrin inflammasome in vitro by interacting with the B30.2 domain (coded by exon 10).

• #51 Familial Mediterranean fever – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/familial-mediterranean-fever/symptoms-causes/syc-20372470

  Familial Mediterranean fever is caused by a gene change (mutation) that’s passed from parents to children. The gene change affects the function of an immune system protein called pyrin, causing problems in regulating inflammation in the body. […] In people with FMF, change occurs in a gene called MEFV. Many different changes in MEFV are linked to FMF. Some changes may cause very severe cases, while others may result in milder signs and symptoms. […] It’s unclear what exactly triggers attacks, but they may occur with emotional stress, menstruation, exposure to cold, and physical stress such as illness or injury.

• #52 Familial Mediterranean Fever – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/hereditary-periodic-fever-syndromes/familial-mediterranean-fever

  Daily prophylactic colchicine should be initiated as soon as the diagnosis is made to prevent attacks as well as amyloidosis. Colchicine provides complete remission or distinct improvement in almost 95% of patients. If attacks or subclinical inflammation persist, the colchicine dose should be increased. […] Patients who are colchicine-resistant or -intolerant may be treated with IL-1 inhibitors (anakinra once a day, rilonacept weekly, or canakinumab every 4 weeks). However, the role of IL-1 inhibitors in preventing amyloidosis remains unknown, and patients taking IL-inhibitors should continue taking colchicine if tolerated.

• #53 Familial Mediterranean fever – Wikipedia

  https://en.wikipedia.org/wiki/Familial_Mediterranean_fever

  In its basal state, pyrin is kept inactive by a chaperone protein (belonging to the family of 14.3.3 proteins) linked to pyrin through phosphorylated serine residues. The dephosphorylation of pyrin is an essential prerequisite for the activation of the pyrin inflammasome. Inactivation of RhoA GTPases (by bacterial toxins, for example) leads to the inactivation of PKN1 / PKN2 kinases and dephosphorylation of pyrin. In healthy subjects, the dephosphorylation step alone does not cause activation of the pyrin inflammasome. In contrast, in FMF patients, the dephosphorylation of serines is sufficient to trigger the activation of the pyrin inflammasome. This suggests that there is a two-level regulation and that the second regulatory mechanism (independent of (de)phosphorylation) is deficient in FMF patients. This deficient mechanism is probably located at the level of the B30.2 domain (exon 10) where most of the pathogenic mutations associated with FMF are located. It is probably the interaction of this domain with the cytoskeleton (microtubules) that is failing, as suggested by the efficacy of colchicine.

• #54 Familial Mediterranean Fever (FMF): What It Is & Symptoms

  https://my.clevelandclinic.org/health/diseases/familial-mediterranean-fever

  The standard treatment for familial Mediterranean fever is an anti-inflammatory medication called colchicine. It works by inhibiting the activity of white blood cells called neutrophils, which play a role in inflammation. Colchicine can help prevent or reduce the frequency of FMF attacks and its complications. […] Many people stop having inflammatory episodes with medication. Others have fewer, milder ones.

• #55 Familial Mediterranean Fever – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/hereditary-periodic-fever-syndromes/familial-mediterranean-fever

  Daily prophylactic colchicine should be initiated as soon as the diagnosis is made to prevent attacks as well as amyloidosis. Colchicine provides complete remission or distinct improvement in almost 95% of patients. If attacks or subclinical inflammation persist, the colchicine dose should be increased. […] Patients who are colchicine-resistant or -intolerant may be treated with IL-1 inhibitors (anakinra once a day, rilonacept weekly, or canakinumab every 4 weeks). However, the role of IL-1 inhibitors in preventing amyloidosis remains unknown, and patients taking IL-inhibitors should continue taking colchicine if tolerated.

• #56 FAMILIAL MEDITERRANEAN FEVER: ASSESSING THE OVERALL CLINICAL IMPACT AND FORMULATING TREATMENT PLANS | Mediterranean Journal of Hematology and Infectious Diseases

  https://www.mjhid.org/index.php/mjhid/article/view/2019.027

  Recurrent self-limited attacks of fever and short-lived inflammation in the serosal membranes, joints and skin are the leading features of familial Mediterranean fever (FMF), the most common autoinflammatory disorder in the world, transmitted as autosomal recessive trait caused by MEFV gene mutations. Their consequence is an abnormal function of pyrin, a natural repressor of inflammation, apoptosis and release of cytokines. FMF-related mutant pyrins are hypophosphorylated following RhoA GTPases impaired activity and show a propensity to relapsing uncontrolled systemic inflammation with inappropriate response to inflammatory stimuli and leukocyte spread to serosal membranes, joints or skin. […] The influence of epigenetic and/or environmental factors can contribute to the variable penetrance and phenotypic heterogeneity of FMF. […] Many recent studies have also shown that anti-interleukin-1 treatment is actually the best therapeutic option for FMF patients nonresponsive or intolerant to colchicine.

• #57 Familial Mediterranean Fever – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/hereditary-periodic-fever-syndromes/familial-mediterranean-fever

  There is strong evidence that Yersinia pestis, the cause of bubonic plague, led to the positive selection of FMF-associated MEFV mutations. These mutations confer a survival advantage to certain people who harbor Yersinia pestis. […] Diagnosis of familial Mediterranean fever is mainly clinical based on Tel HaShomer criteria, but genetic testing is available and is particularly useful in evaluation of atypical cases. However, current genetic testing is not infallible; some patients with phenotypically unmistakeable FMF have only a single mutated gene or occasionally no evident mutations in the MEFV gene. About 10 to 20% of patients who meet the diagnostic criteria for FMF do not have MEFV mutations, which suggests epigenetic and environmental factors contribute to the disease pathogenesis.

• #58 Familial Mediterranean Fever: A Retrospective Clinical and Molecular Study in the East of Anatolia Region of Turkey

  https://openrheumatologyjournal.com/VOLUME/4/PAGE/1/FULLTEXT/

  Familial Mediterranean Fever (FMF) is an autoinflammatory periodic disorder. The most important features were the predominance of the M694V and E148Q mutations in patient group and the earlier of onset of the disease in M694V mutation carriers compared with the carriers of other mutations (P=0.00). The gene linked to FMF, called MEFV, was cloned from chromosome 16p using positional cloning and some of the mutations associated with the disease were identified. The protein encoded by the MEFV gene, termed pyrin or marenostrin, includes a PYRIN domain (PYD), which has been already analyzed crystallographically. Pyrin presumably participates in a complex interplay with the PYD protein superfamily, lipopolysaccharide (LPS) via Toll-like receptor family and procaspase-1 activation, and is implicated in the homeostatic control of inflammation through leukocyte apoptosis, IL-1, and NF-B pathway activation. Genotype-phenotype correlation, thoroughly studied over the past few years, suggested that mutations located within the mutational hotspots in codons 680 and 694 are associated with severe disease, early onset, high frequency of attacks, the necessity of a high dose of colchicine to control attacks, and frequent occurrence of amyloidosis in untreated patients. The present study aim to investigate the twelve most common MEFV mutations frequency in the east of Anatolia in Turkey and to compared these results with the studies performed in other regions of Turkey. The most common mutation in patients group was M694V, followed by E148Q, V726A and M680I. The mean age of onset of the disease was the lower in M694V mutation carrier (9.3 years) compared with other mutations carriers (13.2 years) (P = 0.00) by Mann-Whitney U test. E148Q mutation was detected in 159 patients, 37 patients were compound heterozygous and 123 patients were heterozygous. The frequencies of E148Q, M694V, M694I, V726A and P369S mutation carriage were 12.6% (with 13/206 allele frequency), 5.8% (6/206), 1.9% (2/206), 1.9% (2/206) and 0.9% (1/206), respectively. The distribution of the eight most common mutations among healthy individuals was significantly different from that found in patients. The overall allele frequency calculated from the mutation frequencies in the healthy controls was 12% for E148Q. Compared with healthy controls (12%), FMF patients (19.1%) showed high E148Q allele frequencies by fishers exact test (p = 0.001). It became evident that FMF is not fully recessive and some heterozygous patients tend to have relatively mild disease, but the disease cannot be distinguished clinically from that in homozygous patients. Our results are highly consistent with the existence of a clinical phenotype among some patients heterozygous for FMF and, thus, have several important implications. The molecular analysis of the MEFV gene is the only objective test that confirms the diagnosis in our cohort. A genotype-phenotype correlation showed a relationship between the M694V mutation and the earlier of onset of the disease.

• #59 Familial Mediterranean fever: current perspectives | JIR

  https://www.dovepress.com/familial-mediterranean-fever-current-perspectives-peer-reviewed-fulltext-article-JIR

  The pathogenic role of E148Q on exon 2 (one of the most common alterations in the MEFV gene) still remains controversial. It might be a polymorphism since it is present in 1% of the healthy population. […] The recent evidence-based recommendations for genetic diagnosis of FMF are as follows: FMF is a clinical diagnosis, which can be supported but not excluded by genetic testing. […] The prognosis of a compliant FMF patient is now excellent thanks to the advances in management of FMF and the use of biologics, especially anti-IL-1 drugs.

• #60 Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7672358/

  Phosphorylated pyrin binds to inhibitory 14-3-3 proteins and this process retains pyrin in an inactive state that prevents formation of the pyrin inflammasome. […] In FMF, mutations in MEFV gene impair interaction of pyrin with microtubules, PKN and 14-3-3 proteins facilitating formation of a proinflammatory pyrin inflammasome. […] The most common MEFV variant is M694V (c.2080AG) in FMF endemic areas. […] Most of the pathogenic/likely pathogenic variants are located on exon 10 which encodes B30.2/SPRY domain, responsible for the activation of caspase-1.

• #61 Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7672358/

  Familial Mediterranean fever (FMF) is caused by gain of function mutations of MEFV gene which encodes an immune regulatory protein, pyrin. […] Elucidation of some of the mechanisms underlying FMF pathogenesis has led to the discovery of critical immune pathways including intracellular danger sensors, inflammasomes, pyroptosis and NETosis, thereby transforming the understanding of mechanisms and treatment of prevalent inflammatory, metabolic, cardiovascular and degenerative diseases. […] Unusually for a disease largely inherited in an autosomal recessive fashion, FMF results from gain of function mutations of Mediterranean fever gene (MEFV), located on chromosome 16 (16p13.3). […] Upon activation, pyrin oligomerizes with other cellular proteins, forming a macromolecular complex called pyrin inflammasome that activates caspase-1 which, in turn, mediates the release of pro-inflammatory IL-1 and IL-18 from their inactive precursors and pyroptosis via the gasdermin D pathway.

• #62 Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review

  https://journals.tubitak.gov.tr/medical/vol50/iss10/3/

  Familial Mediterranean fever (FMF) (OMIM #249100) is the most common hereditary autoinflammatory disease in the world. FMF is caused by gain of function mutations of MEFV gene which encodes an immune regulatory protein, pyrin. […] Elucidation of some of the pathogenic mechanisms has led to the discovery of pathways involved in inflammatory, metabolic, cardiovascular and degenerative diseases. […] The use of next generation sequencing in FMF has revealed many new gene variants whose clinical significance may be clarified by developing functional assays and biomarkers.

• #63 Updates on the role of epigenetics in familial mediterranean fever (FMF) | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-024-03098-w

  Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease caused by mutations in the MEFV (Mediterranean Fever) gene that affects people originating from the Mediterranean Sea. The high variability in severity and clinical manifestations observed not only between ethnic groups but also between and within families is mainly related to MEFV allelic heterogeneity and to some modifying genes. […] In addition to the genetic factors underlying FMF, the environment plays a significant role in the development and manifestation of this disease through various epigenetic mechanisms, including DNA methylation, histone modification, and noncoding RNAs. Indeed, epigenetic events have been identified as an important pathophysiological determinant of FMF and co-factors shaping the clinical picture and outcome of the disease.

• #64 Assessment of Circulating Microribonucleic Acids in Patients With Familial Mediterranean Fever | Volume 35 – Issue 1 – March 2020 | Archives of Rheumatology

  https://www.archivesofrheumatology.org/full-text/1077

  In a study about the relationship between genotype and plasma miRNA expressions in patients with FMF, it has been shown that the plasma mRNA-452 expressions were increased in M694V (+) patients (more pronounced in homozygous ones) and associated with worse clinical course. […] Our findings suggest that miRNA-155 may be involved in the pathogenesis of FMF with a negative regulatory effect through targeting SOCS1, and that the reduction of plasma levels may be related to disease exacerbation. […] Our results showed that the plasma miRNA-155 and miRNA-204 levels are significantly decreased in patients with FMF and it was thought that these molecules may have roles in the pathogenesis of FMF. Increased plasma levels of miRNA-16 and miRNA-451 in FMF patients also suggest that these molecules may be associated with disease pathogenesis.

• #65 miR-21 and cathepsin B in familial Mediterranean fever: novel findings regarding their impact on disease severity | BMJ Paediatrics Open

  https://bmjpaedsopen.bmj.com/content/9/1/e003064

  These findings highlight the role of genetic background and molecular mechanisms in the pathogenesis of FMF. Moreover, miR-21 expression and cathepsin B levels are independent predictors of disease severity. […] In this regard, cathepsin B and miR-21 were identified as potential molecules for IL-1 release in our study and may act as independent predictors of disease severity. […] Our findings suggest that miR-21-5p and IL-1 play key roles in subclinical inflammation, and these molecules might be a potential therapeutic target.

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