Abstract
Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disorder with recurrent fever, abdominal pain, serositis, articular manifestations, erysipelas-like erythema, and renal complications as its main features. Caused by the mutations in the MEditerranean FeVer (MEFV) gene, it mainly affects people of Mediterranean descent with a higher incidence in the Turkish, Jewish, Arabic, and Armenian populations. As our understanding of FMF improves, it becomes clearer that we are facing with a more complex picture of FMF with respect to its pathogenesis, penetrance, variant type (gain-of-function vs. loss-of-function), and inheritance. In this study, MEFV gene analysis results and clinical findings of 27,504 patients from 35 universities and institutions in Turkey and Northern Cyprus are combined in an effort to provide a better insight into the genotype-phenotype correlation and how a specific variant contributes to certain clinical findings in FMF patients. Our results may help better understand this complex disease and how the genotype may sometimes contribute to phenotype. Unlike many studies in the literature, our study investigated a broader symptomatic spectrum and the relationship between the genotype and phenotype data. In this sense, we aimed to guide all clinicians and academicians who work in this field to better establish a comprehensive data set for the patients. One of the biggest messages of our study is that lack of uniformity in some clinical and demographic data of participants may become an obstacle in approaching FMF patients and understanding this complex disease.
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References
Accetturo M, D’Uggento AM, Portincasa P, Stella A (2020) Improvement of MEFV gene variants classification to aid treatment decision making in familial Mediterranean fever. Rheumatol (United Kingdom) 59:754–761. https://doi.org/10.1093/rheumatology/kez332
Akpolat T, Özkaya O, Özen S (2012) Homozygous M694V as a risk factor for amyloidosis in Turkish FMF patients. Gene 492:285–289. https://doi.org/10.1016/j.gene.2011.10.012
Alghamdi M (2017) Familial Mediterranean fever, review of the literature. Clin Rheumatol 36:1707–1713. https://doi.org/10.1007/s10067-017-3715-5
Atoyan S, Hayrapetyan H, Sarkisian T, Ben-Chetrit E (2016) MEFV and SAA1 genotype associations with clinical features of familial Mediterranean fever and amyloidosis in Armenia. Clin Exp Rheumatol 34(6 Suppl 102):72–76. http://www.ncbi.nlm.nih.gov/pubmed/27791951
Bakkaloglu A, Duzova A, Ozen S, et al. (2004) Influence of Serum Amyloid A (SAA1) and SAA2 gene polymorphisms on renal amyloidosis, and on SAA/C-reactive protein values in patients with familial mediterranean fever in the Turkish population. J Rheumatol 31
Belmahi L, Cherkaoui IJ, Hama I, Sefiani A (2012) MEFV mutations in Moroccan patients suffering from familial Mediterranean Fever. Rheumatol Int 32:981–984. https://doi.org/10.1007/s00296-010-1732-7
Ben-Chetrit E, Lerer I, Malamud E et al (2000) The E148Q mutation in the MEFV gene: is it a disease-causing mutation or a sequence variant? Hum Mutat 15:385–386. https://doi.org/10.1002/(SICI)1098-1004(200004)15:4%3c385::AID-HUMU22%3e3.0.CO;2-A
Bernot A, Clepet C, Dasilva C et al (1997) A candidate gene for familial Mediterranean fever. Nat Genet 17:25–31. https://doi.org/10.1038/ng0997-25
Beşer ÖF, Kasapçopur Ö, Çokuǧraş FÇ et al (2013) Association of inflammatory bowel disease with familial mediterranean fever in Turkish children. J Pediatr Gastroenterol Nutr 56:498–502. https://doi.org/10.1097/MPG.0b013e31827dd763
Canpolat M, Gumus H, Gunduz Z et al (2017) Erratum: Neurological manifestations in familial mediterranean fever: Results of 22 children from a reference Center in Kayseri, an Urban Area in Central Anatolia, Turkey (Neuropediatrics (2017) 48:2 (79) DOI: 10.1055/s-0036-1593374). Neuropediatrics 48:402
Cekin N, Akyurek ME, Pinarbasi E, Ozen F (2017) MEFV mutations and their relation to major clinical symptoms of Familial Mediterranean Fever. Gene 626:9–13. https://doi.org/10.1016/j.gene.2017.05.013
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. https://doi.org/10.1016/j.immuni.2011.02.020
Chae JJ, Wood G, Masters SL et al (2006) 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 103:9982–9987. https://doi.org/10.1073/pnas.0602081103
Chae JJ, Wood G, Richard K et al (2008) The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 and activates NF-κB through its N-terminal fragment. Blood 112:1794–1803. https://doi.org/10.1182/blood-2008-01-134932
Consortium TIFMF (1997) Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90:797–807. https://doi.org/10.1016/s0092-8674(00)80539-5
Domingo C, Touitou I, Bayou A et al (2000) Familial Mediterranean fever in the “Chuetas” of Mallorca: a question of Jewish origin or genetic heterogeneity. Eur J Hum Genet 8:242–246. https://doi.org/10.1038/sj.ejhg.5200462
Dundar M, Kiraz A, Balta B et al (2013) The role of TNF-α and PAI-1 gene polymorphisms in familial Mediterranean fever. Mod Rheumatol 23:140–145. https://doi.org/10.3109/s10165-012-0687-9
Ekinci RMK, Balcı S, Akay E et al (2019) Frequency of functional gastrointestinal disorders in children with familial Mediterranean fever. Clin Rheumatol 38:921–926. https://doi.org/10.1007/s10067-019-04452-1
Eyal O, Shinar Y, Pras M, Pras E (2020) Familial Mediterranean fever: penetrance of the p.[Met694Val];[Glu148Gln] and p.[Met694Val];[=] genotypes. Hum Mutat 41:1866–1870. https://doi.org/10.1002/humu.24090
Gangemi S, Manti S, Procopio V et al (2018) Lack of clear and univocal genotype-phenotype correlation in familial Mediterranean fever patients: a systematic review. Clin Genet 94:81–94
Gumus E (2018) The frequency of MEFV gene mutations and genotypes in Sanliurfa Province, South-Eastern region of Turkey, after the Syrian Civil War by using next generation sequencing and report of a novel exon 4 mutation (I423T). J Clin Med 7:105. https://doi.org/10.3390/jcm7050105
Gunesacar R, Celik MM, Arica V et al (2014) Frequency of MEFV gene mutations in Hatay province, Mediterranean region of Turkey and report of a novel missense mutation (I247V). Gene 546:195–199. https://doi.org/10.1016/j.gene.2014.06.019
Hashkes PJ, Spalding SJ, Giannini EH et al (2012) Rilonacept for colchicine-resistant or -intolerant familial Mediterranean fever: a randomized trial. Ann Intern Med 157:533–541. https://doi.org/10.7326/0003-4819-157-8-201210160-00003
Infevers: an online database for autoinflammatory mutations. Copyright. Available at https://infevers.umai-montpellier.fr/ Accessed (June 3rd 2021) Infevers. https://infevers.umai-montpellier.fr/web/. Accessed 3 Jun 2021
Karacan İ, Uğurlu S, Tolun A et al (n.d.) Other autoinflammatory disease genes in an FMF-prevalent population: a homozygous MVK mutation and a novel heterozygous TNFRSF1A mutation in two different Turkish families with clinical FMF. Clin Exp Rheumatol 35:75–81
Kilic A, Varkal A, Durmus MS, et al (2015) Relationship between clinical findings and genetic mutations in patients with familial Mediterranean fever. Pediat Rheumatol, 13(1):59. https://doi.org/10.1186/s12969-015-0057-1
Kim JR, Kim HA (2020) Molecular mechanisms of sex-related differences in arthritis and associated pain. Int. J. Mol. Sci. 21:1–21
Little S (1995) Amplification-refractory mutation system (ARMS) analysis of point mutations. Curr Protoc Hum Genet 7https://doi.org/10.1002/0471142905.hg0908s07
Livneh A, Langevitz P, Zemer D et al (1997) Criteria for the diagnosis of familial mediterranean fever. Arthritis Rheum 40:1879–1885. https://doi.org/10.1002/art.1780401023
Mansfield E, Chae JJ, Komarow HD et al (2001) The familial Mediterranean fever protein, pyrin, associates with microtubules and colocalizes with actin filaments. Blood 98:851–859. https://doi.org/10.1182/blood.V98.3.851
Mikula M, Buller A, Sun W, Strom CM (2008) Prevalence of known mutations in the familial Mediterranean fever gene (MEFV) in various carrier screening populations. Genet Med 10:349–352. https://doi.org/10.1097/GIM.0b013e3181723cc8
Milenković J, Vojinović J, Debeljak M et al (2016) Distribution of MEFV gene mutations and R202Q polymorphism in the Serbian population and their influence on oxidative stress and clinical manifestations of inflammation. Pediatr Rheumatol 14:1–9. https://doi.org/10.1186/s12969-016-0097-1
Moghaddas F, Llamas R, De Nardo D et al (2017) A novel pyrin-associated autoinflammation with neutrophilic dermatosis mutation further defines 14–3-3 binding of pyrin and distinction to familial Mediterranean fever. Ann Rheum Dis 76:2085–2094. https://doi.org/10.1136/annrheumdis-2017-211473
Mor A, Gal R, Livneh A (2003) Abdominal and digestive system associations of familial Mediterranean fever. Am. J. Gastroenterol. 98:2594–2604
Ortona E, Pierdominici M, Maselli A et al (2016) Monographic section sex-based differences in autoimmune diseases. Ann Ist Super Sanità 52:205–212. https://doi.org/10.4415/ANN_16_02_12
Ozdogan H, Ugurlu S (2019) Familial Mediterranean fever. Presse Med 48:e61–e76. https://doi.org/10.1016/j.lpm.2018.08.014
Ozen S, Batu ED (2015) The myths we believed in familial mediterranean fever: what have we learned in the past years? Semin Immunopathol 37:363–369. https://doi.org/10.1007/s00281-015-0484-6
Özen S, Batu ED, Demir S (2017) Familial mediterranean fever: recent developments in pathogenesis and new recommendations for management. Front Immunol 8:253. https://doi.org/10.3389/fimmu.2017.00253
Ozen S, Bilginer Y (2014) A clinical guide to autoinflammatory diseases: familial Mediterranean fever and next-of-kin. Nat Rev Rheumatol 10:135–147
Oztuzcu S, Ulaşlı M, Ergun S et al (2014) Screening of common and novel familial mediterranean fever mutations in south-east part of Turkey. Mol Biol Rep 41:2601–2607. https://doi.org/10.1007/s11033-014-3118-5
Papadopoulos VP, Giaglis S, Mitroulis I, Ritis K (2008) The population genetics of familial mediterranean fever: a meta-analysis study. Ann Hum Genet 72:752–761. https://doi.org/10.1111/j.1469-1809.2008.00471.x
Richards N, Schaner P, Diaz A et al (2001) Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis. J Biol Chem 276:39320–39329. https://doi.org/10.1074/jbc.m104730200
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. Rheumatol (United Kingdom) 56:209–213. https://doi.org/10.1093/rheumatology/kew058
Saito D, Hibi N, Ozaki R et al (2020) MEFV gene-related enterocolitis account for some cases diagnosed as inflammatory bowel disease unclassified. Digestion 101:785–793. https://doi.org/10.1159/000502640
Shinar Y, Ceccherini I, Rowczenio D et al (2020) ISSAID/EMQN best practice guidelines for the genetic diagnosis of monogenic autoinflammatory diseases in the Next-Generation Sequencing Era. Clin Chem 66:525–536. https://doi.org/10.1093/clinchem/hvaa024
Shinar Y, Obici L, Aksentijevich I et al (2012) Guidelines for the genetic diagnosis of hereditary recurrent fevers. Ann. Rheum. Dis. 71:1599–1605
Shohat M (2020) Summary GeneReview scope diagnosis suggestive findings. https://www.ncbi.nlm.nih.gov/books/NBK1227/. Accessed 3 Jun 2021
Shohat M (1993) Familial Mediterranean fever. University of Washington, Seattle
Shohat M, Halpern GJ (2011) Familial Mediterranean sever—a review. Genet Med 13:487–498. https://doi.org/10.1097/gim.0b013e3182060456
Siegal S (1945) Benign paroxysmal peritonitis. Ann Intern Med 23:1. https://doi.org/10.7326/0003-4819-23-1-1
Soriano A, Manna R (2012) Familial Mediterranean fever: new phenotypes. Autoimmun Rev 12:31–37. https://doi.org/10.1016/j.autrev.2012.07.019
Soylemezoglu O, Arga M, Fidan K et al (2010) Unresponsiveness to colchicine therapy in patients with familial mediterranean fever homozygous for the M694V mutation. J Rheumatol 37:182–189. https://doi.org/10.3899/jrheum.090273
Soylemezoglu O, Kandur Y, Duzova A et al (2015) Familial Mediterranean fever with a single MEFV mutation: comparison of rare and common mutations in a Turkish paediatric cohort. Clin Exp Rheumatol 33:152–155
Stehlik C, Fiorentino L, Dorfleutner A et al (2002) The PAAD/PYRIN-family protein ASC is a dual regulator of a conserved step in nuclear factor κB activation pathways. J Exp Med 196:1605–1615. https://doi.org/10.1084/jem.20021552
Tomiyama N, Higashiuesato Y, Oda T et al (2008) MEFV mutation analysis of familial Mediterranean fever in Japan. Clin Exp Rheumatol 26:13–17
Topaloglu R, Batu ED, Yıldız Ç et al (2018) Familial Mediterranean fever patients homozygous for E148Q variant may have milder disease. Int J Rheum Dis 21:1857–1862. https://doi.org/10.1111/1756-185X.12929
Touitou I, Picot M-C, Domingo C, et al (2001) The MICA region determines the first modifier locus in familial Mediterranean fever. Arthritis Rheum 44(1):163–169. https://doi.org/10.1002/1529-0131(200101)44:1<163::AID-ANR20>3.0.CO;2-Z
Tunca M, Ozdogan H, Kasapcopur O et al (2005) Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore) 84:1–11. https://doi.org/10.1097/01.md.0000152370.84628.0c
van der Hilst JCH, Moutschen M, Messiaen PE et al (2016) Efficacy of anti-IL-1 treatment in familial mediterranean fever: a systematic review of the literature. Biol Targets Ther 10:75–80. https://doi.org/10.2147/BTT.S102954
Watad A, Bragazzi NL, Adawi M et al (2019) FMF is associated with a wide spectrum of MHC class I- and allied SpA disorders but not with classical MHC class II-associated autoimmune disease: insights from a large cohort study. Front Immunol 10:2733. https://doi.org/10.3389/fimmu.2019.02733
Weinert C, Morger D, Djekic A, et al. (2015) Crystal structure of TRIM20 C-terminal coiled-coil/B30.2 fragment: implications for the recognition of higher order oligomers. Sci Rep 5 https://doi.org/10.1038/srep10819
Yaşar Bilge NŞ, Sari İ, Solmaz D et al (2019) The distribution of MEFV mutations in Turkish FMF patienmulticenter study representing results of anatolia. Turk J Med Sci 49:472–477. https://doi.org/10.3906/sag-1809-100
Yigit S, Karakus N, Tasliyurt T et al (2012) Significance of MEFV gene R202Q polymorphism in Turkish familial Mediterranean fever patients. Gene 506:43–45. https://doi.org/10.1016/j.gene.2012.06.074
Yildirim ME, Kurtulgan HK, Ozdemir O et al (2019) Prevalence of MEFV gene mutations in a large cohort of patients with suspected familial Mediterranean fever in Central Anatolia. Ann Saudi Med 39:382–387. https://doi.org/10.5144/0256-4947.2019.382
Yilmaz G, Senes M, Kayalp D, Yucel D (2016) Is Turkish MEFV mutations spectrum different among regions? J Clin Lab Anal 30:641–644. https://doi.org/10.1002/jcla.21915
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The authors would like to thank all clinicians and institutions who made substantial contributions to providing the patients within the scope of this consortium study.
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Dundar, M., Fahrioglu, U., Yildiz, S.H. et al. Clinical and molecular evaluation of MEFV gene variants in the Turkish population: a study by the National Genetics Consortium. Funct Integr Genomics 22, 291–315 (2022). https://doi.org/10.1007/s10142-021-00819-3
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DOI: https://doi.org/10.1007/s10142-021-00819-3