Molecular Genetics of Familial Mediterranean Fever

Abstract

Familial Mediterranean fever (FMF) is an autoinflammatory disease, which is prevalent in populations of the Mediterranean ancestry. Traditionally, FMF was considered as an autosomal recessive genetic disorder; however, several studies showed that a heterozygote state might also result in disease. Mutations responsible for the disease are located in the MEFV gene encoding a protein called pyrin/marenostrin/TRIM20. FMF is characterised by seemingly unprovoked periodic activation of innate immunity, with fever and serosal inflammation. Among more than 300 mutations in the MEFV gene, five mutations (M694V, V726A, M680I, M694I and E148Q) are the most common in classically affected populations (Armenians, Arabs, Jews and Turks). Disease severity depends on specific MEFV mutations and also on a number of other genetic or environmental modifiers. Certain evolutionary aspects of the disease were intensively investigated including the origin of major MEFV mutations, structure‐and‐function and evolution of pyrin and potential selective advantage of heterozygous carriage.

Key Concepts

  • Familial Mediterranean fever (FMF, MIM 249100) is an autoinflammatory genetic disease, and it is prevalent in populations of Mediterranean origin.
  • The highest incidence of the disorder is documented in four ethnic groups Armenians, Arabs, Jews and Turks, which are considered as ‘classically affected populations’.
  • Clinical manifestations of FMF include periodic occurrence of fever and inflammation in the peritoneum, synovium or pleura. Renal amyloidosis is the most serious complication of the disease.
  • The disease is caused by mutations in the MEFV (MEditerraneanFeVer) gene, which is composed of 10 exons and located on chromosome 16 (16p13.3).
  • MEFV encodes a protein named pyrin or marenostrin or TRIM20, which is a key component of innate immunity.
  • Presently, more than 300 MEFV mutations have been identified. Five mutations (M694V, V726A, M680I and M694I in exon 10 and E148Q in exon 2) are most frequent in classically affected populations.
  • Severity of FMF depends on specific MEFV mutations as well as on a number of other genetic and environmental modifiers.
  • The most common MEFV mutations display a relatively ancient origin, with the subsequent penetration to other populations following migratory and interbreeding processes.
  • The high carriage rate of MEFV mutations in classically affected populations may be explained by a potential selection for the heterozygote genotype, which may have conferred some sort of selective advantage for populations in the area but currently there is no proof for this.

Keywords: Familial Mediterranean fever; MEFV; Mediterranean basin; pyrin; evolution of pyrin

Figure 1. The structure of MEFV gene and its product, pyrin. (a) Structure of MEFV gene; exon 10, where the most of mutations are located, is highlighted in red. (b) Domain organisation of pyrin protein. PYD, pyrin domain; bZIP, bZIP transcription factor basic domain; BB, B‐box domain; CC, coiled‐coil domain and B30.2, C‐terminal B30.2/SPRY/rfp domain.
Figure 2. Phylogenetic reconstruction of pyrin evolution produced with minimum evolution method using the amino acid sequences predicted. The amino acid sequence used to retrieve homologous sequences from GenBank is highlighted in yellow. The scale bar is in fixed amino acid substitutions per sequence position. Only the primate clade is expanded while for the other clades only the number of leaves within a clade is given.
close

References

Al‐Alami RJ, Tayeh MK, Najib DA, et al. (2003) Familial Mediterranean fever mutation frequencies and carrier rates among a mixed Arabic population. Saudi Medical Journal 24: 1055–1059.

Atoyan S, Hayrapetyan H, Sarkisian T and Ben‐Chetrit E (2016) MEFV and SAA1 genotype associations with clinical features of familial Mediterranean fever and amyloidosis in Armenia. Clinical and Experimental Rheumatology 34 (6 Suppl 102): 72–76.

Belmahi L, Sefiani A, Fouveau C, et al. (2006) Prevalence and distribution of MEFV mutations among Arabs from the Maghreb patients suffering from familial Mediterranean fever. Comptes Rendus Biologies 329: 71–74.

Belmahi L, Cherkaoui IJ, Hama I and Sefiani A (2012) MEFV mutations in Moroccan patients suffering from familial Mediterranean fever. Rheumatology International 32 (4): 981–984.

Ben‐Chetrit E and Touitou I (2009) Familial Mediterranean fever in the world. Arthritis Care & Research 61: 1447–1453.

Ben‐Zvi I, Herskovizh C, Kukuy O, et al. (2015) Familial Mediterranean fever without MEFV mutations: a case‐control study. Orphanet Journal of Rare Diseases 10: 34.

Berkun Y, Karban A, Padeh S, et al. (2012) NOD2/CARD15 gene mutations in patients with familial Mediterranean fever. Seminars in Arthritis and Rheumatism 42 (1): 84–88.

Chae JJ, Cho YH, Lee GS, et al. (2011) Gain‐of‐function Pyrin mutations induce NLRP3 protein‐independent interleukin‐1β activation and severe autoinflammation in mice. Immunity 34: 755–768.

D'Cruz AA, Babon JJ, Norton RS, et al. (2013) Structure and function of the SPRY/B30.2 domain proteins involved in innate immunity. Protein Science 22: 1–10.

Diaz A, Hu C, Kastner DL, Schaner P, et al. (2004) 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 and Rheumatism 50: 3679–3689.

El‐Shanti H, Majeed HA and El‐Khateeb M (2006) Familial Mediterranean fever in Arabs. Lancet 367 (9515): 1016–1024.

Etem EO, Deveci SD, Erol D, Yuce H and Elyas H (2010) Familial Mediterranean fever: a retrospective clinical and molecular study in the East of Anatolia region of Turkey. Open Rheumatology Journal 4: 1–6.

Fumagalli M, Cagliani R, Pozzoli U, et al. (2009) A population genetics study of the familial Mediterranean fever gene: evidence of balancing selection under an over dominance regime. Genes and Immunity 10: 678–686.

French FMF Consortium (1997) A candidate gene for familial Mediterranean fever. Nature Genetics 17: 25–31.

Gavrilin MA, Abdelaziz DH, Mostafa M, et al. (2012) Activation of the pyrin inflammasome by intracellular Burkholderia cenocepacia. The Journal of Immunology 188: 3469–3477.

Gershoni‐Baruch R, Shinawi M, Leah K, Badarnah K and Brik R (2001) Familial Mediterranean fever: prevalence, penetrance and genetic drift. European Journal of Human Genetics 9: 634–637.

Gumucio DL, Diaz A, Schaner P, et al. (2002) Fire and ICE: the role of pyrin domain‐containing proteins in inflammation and apoptosis. Clinical and Experimental Rheumatology 20 (Suppl. 26): S45–S53.

Hesker PR, Nguyen M, Kovarova M, et al. (2012) Genetic loss of murine pyrin, the Familial Mediterranean Fever protein, increases interleukin‐1beta levels. PLoS One 7: e511056.

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

Jalkh N, Génin E, Chouery E, et al. (2007) Familial Mediterranean fever in Lebanon: founder effects for different MEFV mutations. Annals of Human Genetics 72: 41–47.

Kim ML, Chae JJ, Park YH, et al. (2015) Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL‐18, not IL‐1β. The Journal of Experimental Medicine 212: 927–938.

Kimura T, Jain A, Choi SW, et al. (2015) TRIM‐mediated precision autophagy targets cytoplasmic regulators of innate immunity. The Journal of Cell Biology 210: 973–989.

Manukyan G and Aminov R (2016) Update on Pyrin functions and mechanisms of Familial Mediterranean Fever. Frontiers in Microbiology 7: 456.

Masters SL, Simon A, Aksentijevich I, et al. (2009) Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annual Review of Immunology 27: 621–628.

Moradian MM, Sarkisian T, Ajrapetyan H and Avanesian N (2010) Genotype‐phenotype studies in a large cohort of Armenian patients with familial Mediterranean fever suggest clinical disease with heterozygous MEFV mutations. Journal of Human Genetics 55 (6): 389–393.

Notarnicola C, Didelot M‐N, Kone‐Paut I, et al. (2002) Reduced MEFV messenger RNA expression in patients with familial Mediterranean fever. Arthritis & Rheumatism 46: 2785–2793.

Onat AM, Oztürk MA, Ozçakar L, et al. (2007) Selective serotonin reuptake inhibitors reduce the attack frequency in familial Mediterranean fever. The Tohoku Journal of Experimental Medicine 211 (1): 9–14.

Ozen S (2009) Changing concepts in familial Mediterranean fever: is it possible to have an autosomal‐recessive disease with only one mutation? Arthritis & Rheumatism 60 (6): 1575–1577.

Papadopoulos VP, Giaglis S, Mitroulis I and Ritis K (2008) The population genetics of familial Mediterranean fever: a meta‐analysis study. Annals of Human Genetics 72: 752–761.

Papin S, Duquesnoy P, Cazeneuve C, et al. (2000) Alternative splicing at the MEFV locus involved in familial Mediterranean fever regulates translocation of the marenostrin/pyrin protein to the nucleus. Human Molecular Genetics 9: 3001–3009.

Pasa S, Altintas A, Devecioglu B, et al. (2008) Familial Mediterranean fever gene mutations in the Southeastern region of Turkey and their phenotypical features. Amyloid 15: 49–53.

Reymond A, Meroni G, Fantozzi A, et al. (2001) The tripartite motif family identifies cell compartments. The EMBO Journal 20 (9): 2140–2151.

Rowczenio DM, Iancu DS, Trojer H, et al. (2017) Autosomal dominant familial Mediterranean fever in Northern European Caucasians associated with deletion of p.M694 residue‐a case series and genetic exploration. Rheumatology (Oxford) 56 (2): 209–213.

Sarkisian T, Ajrapetyan H and Shahsuvaryan G (2005) Molecular study of FMF patients in Armenia. Current Drug Targets. Inflammation and Allergy 4: 113–116.

Schaner P, Richards N, Wadhwa A, et al. (2001) Episodic evolution of pyrin in primates: human mutations recapitulate ancestral amino acid states. Nature Genetics 27: 318–321.

Soylemezoglu O, Arga M, Fidan K, et al. (2010) Unresponsiveness to colchicine therapy in patients with familial Mediterranean fever homozygous for the M694V mutation. The Journal of Rheumatology 37: 182–189.

Stoffels M, Szperl A, Simon A, et al. (2014) MEFV mutations affecting pyrin amino acid 577 cause autosomal dominant autoinflammatory disease. Annals of the Rheumatic Diseases 73: 455–461.

Stoffman N, Magal N, Shohat T, et al. (2000) Higher than expected carrier rates for familial Mediterranean fever in various Jewish ethnic groups. European Journal of Human Genetics 8: 307–310.

Taskiran EZ, Cetinkaya A, Balci‐Peynircioglu B, et al. (2012) The effect of colchicine on pyrin and pyrin interacting proteins. Journal of Cellular Biochemistry 113: 3536–3546.

Tchernitchko DO, Gérard‐Blanluet M, Legendre M, et al. (2006) Intrafamilial segregation analysis of the p.E148Q MEFV allele in familial Mediterranean fever. Annals of the Rheumatic Diseases 65: 1154–1157.

Topaloglu R, Ozaltin F, Yilmaz E, et al. (2005) E148Q is a disease‐causing MEFV mutation: a phenotypic evaluation in patients with familial Mediterranean fever. Annals of the Rheumatic Diseases 64: 750–752.

Touitou I (2001) The spectrum of familial Mediterranean fever (FMF) mutations. European Journal of Human Genetics 9: 473–483.

Touitou I, Picot M‐C, Domingo C, et al. (2001) The MICA region determines the first modifier locus in familial Mediterranean fever. Arthritis & Rheumatism 44: 163–169.

Touitou I, Sarkisian T, Medlej‐Hashim M, et al. (2007) Country as the primary risk factor for renal amyloidosis in familial Mediterranean fever. Arthritis & Rheumatism 56: 1706–1712.

Tunca M, Akar S, Onen F, et al. (2005) Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine 84 (1): 1–11.

Turkcapar N, Tuncali T, Kutlay S, et al. (2007) The contribution of genotypes at the MICA gene triplet repeat polymorphisms and MEFV mutations to amyloidosis and course of the disease in the patients with familial Mediterranean fever. Rheumatology International 27: 545–551.

Xu H, Yang J, Gao W, et al. (2014) Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature 513: 237–241.

Yasunami M, Nakamura H, Agematsu K, et al. (2015) Identification of disease‐promoting HLA class I and protective class II modifiers in Japanese patients with familial Mediterranean fever. PLoS One 10: e0125938.

Yenokyan G and Armenian HK (2012) Triggers for attacks in familial Mediterranean fever: application of the case‐crossover design. American Journal of Epidemiology 175 (10): 1054–1061.

Yilmaz E, Ozen S, Balci B, et al. (2001) Mutation frequency of familial Mediterranean fever and evidence for a high carrier rate in the Turkish population. European Journal of Human Genetics 9: 553–555.

Further Reading

Cattan D (2005) MEFV mutation carriers and diseases other than familial Mediterranean fever: proved and non‐proved associations; putative biological advantage. Current Drug Targets. Inflammation and Allergy 4: 59–66.

Mankan AK, Kubarenko A and Hornung V (2012) Immunology in clinic review series; focus on autoinflammatory diseases: inflammasomes: mechanisms of activation. Clinical and Experimental Immunology 167: 369–381.

Schaner PE and Gumucio DL (2005) Familial Mediterranean fever in the post‐genomic era: how an ancient disease is providing new insights into inflammatory pathways. Current Drug Targets. Inflammation and Allergy 4: 67–76.

Shohat M and Halpern GJ (2011) Familial Mediterranean fever – a review. Genetics in Medicine 13 (6): 487–498.

Simon A and van derMeer JWM (2007) Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes. American Journal of Physiology ‐ Regulatory, Integrative and Comparative Physiology 292: 86–98.

Stiehm ER (2006) Disease versus disease: how one disease may ameliorate another. Pediatrics 117: 184–191.

Ting JP‐Y, Kastner DL and Hoffman HM (2006) CATERPILLERs, pyrin and hereditary immunological disorders. Nature Reviews Immunology 6: 183–195.

Touitou I (2013) Inheritance of autoinflammatory diseases: shifting paradigms and nomenclature. Journal of Medical Genetics 50 (6): 349–359.

Yepiskoposyan L and Harutyunyan A (2007) Population genetics of familial Mediterranean fever: a review. European Journal of Human Genetics 15: 911–916.

Zlotogora J (2007) Multiple mutations responsible for frequent genetic diseases in isolated populations. European Journal of Human Genetics 15: 272–278.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Manukyan, Gayane, Aminov, Rustam, Khachatryan, Zaruhi, and Yepiskoposyan, Levon(Sep 2017) Molecular Genetics of Familial Mediterranean Fever. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021442.pub2]