Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

The regulation of MEFV expression and its role in health and familial Mediterranean fever

Genes & Immunity volume 12, pages 497–503 (2011)Cite this article

Subjects

Abstract

Familial Mediterranean fever (FMF) is a hereditary recurrent fever associated with mutations in the gene MEFV encoding pyrin. It is expressed mainly in neutrophils and macrophages, and modulates the production of the potent pro-inflammatory cytokine interleukin-1β through regulation of nuclear factor-κB and caspase-1. The MEFV gene expression depends on multiple levels of regulation. Sequence variants located in the promoter and at the 3′-untranslated region of the gene modulate this expression. Two studies demonstrated decreased mRNA levels in FMF patients compared with healthy subjects, whereas two others found no significant differences. The diverse experimental settings may have resulted in variable quantification of the 15 splice variants that have been identified recently. Some of these isoforms are regulated by nonsense-mediated decay in both cell- and transcript-specific manner, and may be differentially translated in THP1 cells. In addition, pyrin may be cleaved by caspase 1. The full-length pyrin was less abundant than the cleaved fragment in mononuclear cells from FMF patients than in controls, whereas the opposite was observed in granulocytes. Altogether, the regulation of MEFV expression is more complex than anticipated in both physiological and pathological conditions. Its deregulation is likely to alter the inflammasome function and subsequently result in uncontrolled inflammation as seen in FMF.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Heller H, Kariv J, Sherf L, Sohar E . Familial Mediterranean fever]. Harefuah 1955; 48 (5): 91–94.

    CAS  PubMed  Google Scholar 

  2. The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 1997; 90: 797–807.

    Article  Google Scholar 

  3. The French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet 1997; 17: 25–31.

    Article  Google Scholar 

  4. Martinon F, Hofmann K, Tschopp J . The pyrin domain: a possible member of the death domain-fold family implicated in apoptosis and inflammation. Curr Biol 2001; 11: R118–R120.

    Article  CAS  Google Scholar 

  5. Pawlowski K, Pio F, Chu Z, Reed JC, Godzik A . PAAD - a new protein domain associated with apoptosis, cancer and autoimmune diseases. Trends Biochem Sci 2001; 26: 85–87.

    Article  CAS  Google Scholar 

  6. Staub E, Dahl E, Rosenthal A . The DAPIN family: a novel domain links apoptotic and interferon response proteins. Trends Biochem Sci 2001; 26: 83–85.

    Article  CAS  Google Scholar 

  7. Kohl A, Grutter MG . Fire and death: the pyrin domain joins the death-domain superfamily. C R Biol 2004; 327: 1077–1086.

    Article  CAS  Google Scholar 

  8. Stehlik C, Fiorentino L, Dorfleutner A, Bruey JM, Ariza EM, Sagara J et al. The PAAD/PYRIN-family protein ASC is a dual regulator of a conserved step in nuclear factor kappaB activation pathways. J Exp Med 2002; 196: 1605–1615.

    Article  CAS  Google Scholar 

  9. Dowds TA, Masumoto J, Chen FF, Ogura Y, Inohara N, Nunez G . Regulation of cryopyrin/Pypaf1 signaling by pyrin, the familial Mediterranean fever gene product. Biochem Biophys Res Commun 2003; 302: 575–580.

    Article  CAS  Google Scholar 

  10. Masumoto J, Dowds TA, Schaner P, Chen FF, Ogura Y, Li M et al. ASC is an activating adaptor for NF-kappaB and caspase-8-dependent apoptosis. Biochem Biophys Res Commun 2003; 303: 69–73.

    Article  CAS  Google Scholar 

  11. Chae JJ, Wood G, Richard K, Jaffe H, Colburn NT, Masters SL et al. The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 and activates NF-kappaB through its N-terminal fragment. Blood 2008; 112: 1794–1803.

    Article  CAS  Google Scholar 

  12. Yu JW, Wu J, Zhang Z, Datta P, Ibrahimi I, Taniguchi S et al. Cryopyrin and pyrin activate caspase-1, but not NF-kappaB, via ASC oligomerization. Cell Death Differ 2006; 13: 236–249.

    Article  CAS  Google Scholar 

  13. Chae JJ, Wood G, Masters SL, Richard K, Park G, Smith BJ et al. The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1beta production. Proc Natl Acad Sci USA 2006; 103: 9982–9987.

    Article  CAS  Google Scholar 

  14. Papin S, Cuenin S, Agostini L, Martinon F, Werner S, Beer HD et al. The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1beta processing. Cell Death Differ 2007; 14: 1457–1466.

    Article  CAS  Google Scholar 

  15. Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L et al. The tripartite motif family identifies cell compartments. EMBO J 2001; 20: 2140–2151.

    Article  CAS  Google Scholar 

  16. Milhavet F, Cuisset L, Hoffman HM, Slim R, El-Shanti H, Aksentijevich I et al. The infevers autoinflammatory mutation online registry: update with new genes and functions. Hum Mutat 2008; 29: 803–808.

    Article  Google Scholar 

  17. Ben-Chetrit E, Levy M . Familial Mediterranean fever. Lancet 1998; 351: 659–664.

    Article  CAS  Google Scholar 

  18. Chae JJ, Aksentijevich I, Kastner DL . Advances in the understanding of familial Mediterranean fever and possibilities for targeted therapy. Br J Haematol 2009; 146: 467–478.

    Article  CAS  Google Scholar 

  19. Schroder K, Tschopp J . The inflammasomes. Cell 2010; 140: 821–832.

    Article  CAS  Google Scholar 

  20. Centola M, Wood G, Frucht DM, Galon J, Aringer M, Farrell C et al. The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood 2000; 95: 3223–3231.

    CAS  PubMed  Google Scholar 

  21. Tidow N, Chen X, Muller C, Kawano S, Gombart AF, Fischel-Ghodsian N et al. Hematopoietic-specific expression of MEFV, the gene mutated in familial Mediterranean fever, and subcellular localization of its corresponding protein, pyrin. Blood 2000; 95: 1451–1455.

    CAS  PubMed  Google Scholar 

  22. Diaz A, Hu C, Kastner DL, Schaner P, Reginato AM, Richards N et al. Lipopolysaccharide-induced expression of multiple alternatively spliced MEFV transcripts in human synovial fibroblasts: a prominent splice isoform lacks the C-terminal domain that is highly mutated in familial Mediterranean fever. Arthritis Rheum 2004; 50: 3679–3689.

    Article  CAS  Google Scholar 

  23. Papin S, Cazeneuve C, Duquesnoy P, Jeru I, Sahali D, Amselem S . The tumor necrosis factor alpha-dependent activation of the human mediterranean fever (MEFV) promoter is mediated by a synergistic interaction between C/EBP beta and NF kappaB p65. J Biol Chem 2003; 278: 48839–48847.

    Article  CAS  Google Scholar 

  24. Notarnicola C, Boizet-Bonhoure B, de Santa Barbara P, Osta MA, Cattan D, Touitou I . Characterization of new mutations in the 5′-flanking region of the familial Mediterranean fever gene. Genes Immun 2009; 10: 273–279.

    Article  CAS  Google Scholar 

  25. Ustek D, Ekmekci C, Oku B, Cosan F, Cakiris A, Abaci N et al. MEFV gene 3′-UTR Alu repeat polymorphisms in patients with familial Mediterranean fever. Clin Exp Rheumatol 2008; 26 (4 Suppl 50): S72–S76.

    CAS  PubMed  Google Scholar 

  26. Papin S, Duquesnoy P, Cazeneuve C, Pantel J, Coppey-Moisan M, Dargemont C et al. Alternative splicing at the MEFV locus involved in familial Mediterranean fever regulates translocation of the marenostrin/pyrin protein to the nucleus. Hum Mol Genet 2000; 9: 3001–3009.

    Article  CAS  Google Scholar 

  27. Grandemange S, Soler S, Touitou I . Expression of the familial Mediterranean fever gene is regulated by nonsense-mediated decay. Hum Mol Genet 2009; 18: 4746–4755.

    Article  CAS  Google Scholar 

  28. Medlej-Hashim M, Nehme N, Chouery E, Jalkh N, Megarbane A . Novel MEFV transcripts in familial Mediterranean fever patients and controls. BMC Med Genet 2010; 11: 87.

    Article  Google Scholar 

  29. Neu-Yilik G, Kulozik AE . NMD: multitasking between mRNA surveillance and modulation of gene expression. Adv Genet 2008; 62: 185–243.

    Article  CAS  Google Scholar 

  30. Linde L, Boelz S, Nissim-Rafinia M, Oren YS, Wilschanski M, Yaacov Y et al. Nonsense-mediated mRNA decay affects nonsense transcript levels and governs response of cystic fibrosis patients to gentamicin. J Clin Invest 2007; 117: 683–692.

    Article  CAS  Google Scholar 

  31. Notarnicola C, Didelot MN, Kone-Paut I, Seguret F, Demaille J, Touitou I . Reduced MEFV messenger RNA expression in patients with familial Mediterranean fever. Arthritis Rheum 2002; 46: 2785–2793.

    Article  CAS  Google Scholar 

  32. Ustek D, Ekmekci CG, Selcukbiricik F, Cakiris A, Oku B, Vural B et al. Association between reduced levels of MEFV messenger RNA in peripheral blood leukocytes and acute inflammation. Arthritis Rheum 2007; 56: 345–350.

    Article  CAS  Google Scholar 

  33. Mitroulis I, Kourtzelis I, Kambas K, Chrysanthopoulou A, Ritis K . Evidence for the involvement of mTOR inhibition and basal autophagy in familial Mediterranean fever phenotype. Hum Immunol 2010; 72: 135–138.

    Article  Google Scholar 

  34. Booty MG, Chae JJ, Masters SL, Remmers EF, Barham B, Le JM et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum 2009; 60: 1851–1861.

    Article  CAS  Google Scholar 

  35. Cazeneuve C, Papin S, Jeru I, Duquesnoy P, Amselem S . Subcellular localisation of marenostrin/pyrin isoforms carrying the most common mutations involved in familial Mediterranean fever in the presence or absence of its binding partner ASC. J Med Genet 2004; 41: e24.

    Article  CAS  Google Scholar 

  36. Jeru I, Papin S, L'Hoste S, Duquesnoy P, Cazeneuve C, Camonis J et al. Interaction of pyrin with 14.3.3 in an isoform-specific and phosphorylation-dependent manner regulates its translocation to the nucleus. Arthritis Rheum 2005; 52: 1848–1857.

    Article  CAS  Google Scholar 

  37. Abedat S, Urieli-Shoval S, Shapira E, Calko S, Ben-Chetrit E, Matzner Y . Effect of colchicine and cytokines on MEFV expression and C5a inhibitor activity in human primary fibroblast cultures. Isr Med Assoc J 2002; 4: 7–12.

    CAS  PubMed  Google Scholar 

  38. Matzner Y, Abedat S, Shapiro E, Eisenberg S, Bar-Gil-Shitrit A, Stepensky P et al. Expression of the familial Mediterranean fever gene and activity of the C5a inhibitor in human primary fibroblast cultures. Blood 2000; 96: 727–731.

    CAS  PubMed  Google Scholar 

  39. Masters SL, Yao S, Willson TA, Zhang JG, Palmer KR, Smith BJ et al. The SPRY domain of SSB-2 adopts a novel fold that presents conserved Par-4-binding residues. Nat Struct Mol Biol 2006; 13: 77–84.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the CHRU of Montpellier (PHRC2005), the National Human Genome Research Institute, INSERM and Istanbul Faculty of Medicine. We thank the clinicians for providing patient samples, J Tazy for helpful discussion and M Vittal for English editing of the manuscript.

Author information

Authors and Affiliations

  1. Unité médicale des maladies auto-inflammatoires, CHRU de Montpellier, INSERM U844, UM1, Hopital Arnaud de Villeneuve, Montpellier, France

    S Grandemange & I Touitou

  2. National Human Genome Research Institute, Bethesda, MD, USA

    I Aksentijevich

  3. INSERM U933, Université Pierre et Marie Curie-Paris6 UMR S933, Paris, France

    I Jeru

  4. Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

    A Gul

Authors
  1. S Grandemange
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I Aksentijevich
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I Jeru
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Gul
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. I Touitou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to I Touitou.

Ethics declarations

Competing interests

The authors declare no conflict of interest

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grandemange, S., Aksentijevich, I., Jeru, I. et al. The regulation of MEFV expression and its role in health and familial Mediterranean fever. Genes Immun 12, 497–503 (2011). https://doi.org/10.1038/gene.2011.53

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2011.53

Keywords

This article is cited by

Search

Advanced search

Quick links