A HYPOTHETICAL ROLE FOR PLAGUE IN THE SELECTION OF MEFV MUTATION CARRIERS IN THE MEDITERRANEAN AREA
Abstract
Familial Mediterranean fever (FMF) is the most common autoinflammatory disease associated with mutations in the MEFV gene encoding Pyrin. MEFV mutations are frequent in the Mediterranean region. Increased resistance to an infection endemic to this area could have caused a selective advantage for individuals with MEFV mutations. Recent studies have shown that Pyrin is a part of host defense against microorganisms and it gets activated after sensing Rho GTPase inactivation by bacteria such as Clostridium difficile or Yersinia pestis. However, Yersinia species have another effector molecule, YopM which inhibits Pyrin in addition to RhoA modifiers YopE and YopT. Continuously overactive Pyrin in individuals with MEFV mutations could be a good host defense against Yersinia infections. Y. pestis causes plague, which led to a devastating pandemic in the Mediterranean basin. Thus, plague could be the infection which caused a selective biologic advantage for MEFV mutation carriers in this area.
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Ozen S, Batu ED and Demir S. Familial Mediterranean Fever: Recent Developments in Pathogenesis and New Recommendations for Management. Front Immunol 2017;8:253.
Sonmez HE, Batu ED and Ozen S. Familial Mediterranean fever: current perspectives. J Inflamm Res 2016;9:13–20.
Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. Cell 1997;90(4):797–807.
Ozen S, Batu ED. The myths we believed in familial Mediterranean fever: what have we learned in the past years? Semin Immunopathol 2015;37(4):363–369.
Aksentijevich I, Torosyan Y, Samuels J, et al. Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. Am J Hum Genet 1999;64(4):949–962.
Yilmaz E, Ozen S, Balci B, et al. Mutation frequency of Familial Mediterranean Fever and evidence for a high carrier rate in the Turkish population. Eur J Hum Genet 2001;9(7):553–555.
Rogers DB, Shohat M, Petersen GM, et al. Familial Mediterranean fever in Armenians: autosomal recessive inheritence with high gene frequency. Am J Med Genet 1989;34(2):168–172.
Cattan D. MEFV mutation carriers and diseases other than familial Mediterranean fever: proved and non-proved associations; putative biological advantage. Curr Drug Targets Inflamm Allergy 2005;4(1):105–112.
Ross JJ. Goats, germs, and fever: Are the pyrin mutations responsible for familial Mediterranean fever protective against Brucellosis? Med Hypotheses 2007;68(3):499–501.
Ozen S, Balci B, Ozkara S, et al. Is there a heterozygote advantage for familial Mediterranean fever carriers against tuberculosis infections: speculations remain? Clin Exp Rheumatol 2002;20(4 Suppl 26):S57–S58.
Park YH, Wood G, Kastner DL and Chae JJ. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol 2016;17(8):914–921.
Xu H, Yang J, Gao W, et al. Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature 2014;513(7517):237–241.
Chung LK, Park YH, Zheng Y, et al. The Yersinia Virulence Factor YopM Hijacks Host Kinases to Inhibit Type III Effector-Triggered Activation of the Pyrin Inflammasome. Cell Host Microbe 2016;20(3):296–306.
Ratner D, Orning MP, Proulx MK, et al. The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation. PLoS Pathog 2016;12(12):e1006035.
Chae JJ, Cho YH, Lee GS, et al. Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1beta activation and severe autoinflammation in mice. Immunity 2011;34(5):755–768.
Gage KL and Kosoy MY. Natural history of plague: perspectives from more than a century of research. Annu Rev Entomol 2005;50:505–528.
Khan IA. Plague: the dreadful visitation occupying the human mind for centuries. Trans R Soc Trop Med Hyg 2004;98(5):270–277.
Yang R. Plague: Recognition, Treatment, and Prevention. J Clin Microbiol 2018; 56(1):pii:e01519–e01517.
Nikiforov VV, Gao H, Zhou L, Anisimov A. Plague: Clinics, Diagnosis and Treatment. Adv Exp Med Biol 2016;918:293–312.
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