MEFV mutations in Northwest of Iran: a cross sectional study

Document Type : Original Article


1 Faculty of Natural Sciences, Center of Excellence for Biodiversity, University of Tabriz, Tabriz, Iran

2 Gastrointestinal and Liver Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

3 Hematology and Oncology Research Center , Tabriz University of Medical Sciences, Tabriz, Iran


Objective(s):Familial Mediterranean Fever (FMF) is an autosomal recessive disorder characterized by recurrent episodes of fever accompanied by peritonitis, pleurisy, and arthritis. FMF affects mainly Mediterranean populations and is caused by mutations in the familial Mediterranean fever (MEFV) gene. The aim of this study was to identify the frequency and distribution of MEFV mutations in Iranian Azerbaijanis with FMF.

Materials and Methods:Medical records of 1330 Iranian Azerbaijanis who were diagnosed with FMF according to Tel-Hashomer criteria from May 2006 to April 2013 were reviewed and 10 MEFV mutations were found in affected individuals.

Results:243 patients (18.27%) were homozygous, 370 (27.82%) were compound heterozygous and 717 (53.91%) were identified as heterozygous for one of the studied mutations. Of the studied mutations, M694V, E148Q, V726A, M680I, and M694I accounted for 42%, 21%, 19%, 14% and 2% of mutations respectively.

Conclusion:In our study, M694V was found to be the most prevalent mutation. M694I, the most common mutation among Arabs, is rare in this cohort. Allele frequencies of the common mutations in our studied population have some similarities to those of the Turkish population reported previously. However, M680I is less common in our cohort.


1.Ozen S, Aktay N, Lainka E, Duzova A, Bakkaloglu A, Kallinich T. Disease severity in children and adolescents with familial Mediterranean fever: a comparative study to explore environmental effects on a monogenic disease. Ann Rheum Dis 2009; 68:246–248.
2. Baysal T, Peru H, Oran B, Sahin TK, Koksal Y, Karaaslan S. Left ventricular diastolic function evaluated with tissue Doppler imaging in children with familial Mediterranean fever. Clin Rheumatol 2009; 28:23-28.
3. Tavil Y, Ureten K, Oztürk MA, Sen N, Kaya MG, Cemri M, et al. The detailed assessment of left and right ventricular functions by tissue Doppler imaging in patients with familial Mediterranean fever. Clin Rheumatol 2008;27:189–194.
4.Tomiyama N, Higashiuesato Y, Oda T, Baba E, Harada M, Azuma M, et al. MEFV mutation analysis of familial Mediterranean fever in Japan.Clin Exp Rheumatol 2008; 26:13-17.
5. Caliskan M, Gullu H, Yilmaz S, Erdogan D, Unler GK, Ciftci O, et al. Impaired coronary microvascular function in familial Mediterranean fever. Atherosclerosis 2007;195:161–167.
6. Ting J, Kastner D, Hoffman H. CATERPILLERs, pyrin and hereditary immunological disorders. Nat Rev Immunol 2006; 6:183-195.
7. Papin S, Cuenin S, Agostini L, Martinon F, Werner S, Beer H, 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.
8. Karakus N, Yigit S, Inanir A, Inanir S, Toprak H, Okan S. Association between sequence variations of the Mediterranean fever gene and fibromyalgia syndrome in a cohort of Turkish patients. Clin Chim Acta 2012; 24:36-40.
9. Touitou I. The spectrum of familial Mediterranean fever (FMF) mutations. Eur J Hum Genet 2001; 9:473-483.
10. Erten S, Erzurum C, Altunoglu A. Three family members with familial Mediterranean fever carrying the M694V mutation showed different clinical presentations. Intern Med 2012; 51:1765-1768.
11. Aldea A, Calafell F, Arostegui J, Lao O, Rius J, Plaza S, et al. The west side story: MEFV haplotype in Spanish FMF patients and controls, and evidence of high LD and a recombination “hot-spot” at the MEFV locus. Hum Mutat 2004; 23:399.
12. Soriano A, Manna R.Familial mediterranean fever: new phenotypes. Autoimmu Rev 2012; 12: 31-37.
13. Bidari A, Ghavidel-Parsa B, Najmabadi H, Talachian E, Haghighat-Shoar M, Broumand B, et al. Common MEFV mutation analysis in 36 Iranian patients with familial Mediterranean fever: clinical and demographic significance. Mod Rheumatol 2010; 20:566-572.
14. SabokbarT, MalayeriA, AzimiC, RaeeskaramiSR, ZiaeeV, AghighiY, et al. Spectrum of mutations of familial Mediterranean fever gene in Iranian population. Ann Paediatr Rheum2014; 3: 11-17.
15. Bonyadi M, Esmaeili M, Jalali H, Somi M, Ghaffari A, Rafeey M, et al. MEFV mutations in Iranian Azeri Turkish patients with familial Mediterranean fever. Clin Genet 2009; 76:477-480.
16. Stoffman N, Magal N, Shohat T. Higher than expected carrier rates for familial Mediterranean fever in various Jewish ethnic groups. Eur J Hum Genet 2000; 8:307-310.
17. El-Shanti H, Majeed H, El-Khateeb M. Familial Mediterranean fever in Arabs. Lancet 2006; 367:1016 -1024.
18. Yilmaz E, Ozen S, Balci B, Duzova A, Topaloglu R, Besbas N, et al. Mutation frequency of Familial Mediterranean fever and evidence for a high carrier rate in the Turkish population Eur J Hum Genet 2001; 9:553-555.
19. Sarkisian T, Ajrapetian H, Beglarian A. Familial Mediterranean fever in Armenian population. Georgian Med News 2008; 156:105-111.
20. Majeed H, El-Khateeb M, El-Shanti H, Rabaiha Z, Tayeh M, Najib D. The spectrum of familial Mediterranean fever gene mutations in Arabs: report of a large series. Semin Arthritis Rheum 2005; 34:813- 818.
21. Medlej-Hashim M, Serre J, Corbani S, Saab O, Jalkh N, Delague V, et al. Familial Mediterranean fever (FMF) in Lebanon and Jordan: a population genetics study and report of three novel mutations. Eur J Med Genet 2005; 48:412- 420.
22. Jarjour R. Familial mediterranean fever in Syrian patients: MEFV gene mutations and genotype-phenotype correlation. Mol Biol Rep 2010; 37:1-5.
23. Belmahi L, Sefiani A, Fouveau C, Feingold J, Delpech M, Grateau G, et al. Prevalence and distribution of MEFV mutations among Arabs from the Maghreb patients suffering from familial Mediterranean fever. C R Biol 2006; 329:71-74.
24. Tunca M, Akar S, Onen F, Ozdogan H, Kasapcopur O, Yalcinkaya F, et al. Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine 2005; 84:1-11.
25. Dogan H, Koca Y, Erden G, Karaaslan Y, Bozat H. Evaluating MEFV mutation frequency in Turkish familial Mediterranean fever suspected patients and gender correlation: a retrospective study. Mol Biol Rep 2012; 39:6193-6196.
26. Ozdemir O, Sezgin I, Kurtulgan H, Candan F, Koksal B, Sumer H, et al. Prevalence of known mutations in the MEFV gene in a population screening with high rate of carriers. Mol Biol Rep 2011; 38:3195-3200.
27. Demirkaya E, Tunca Y, Gok F, Ozen S, Gul D. A very frequent mutation and remarkable association of R761H with M694V mutations in Turkish FMF patients. Clin Rheumatol 2008; 27:729-732.
28. Dundar M, Emirogullari E, Kiraz A, Taheri S, Baskol M. Common familialm Mediterranean fever gene mutations in a Turkish cohort. Mol Biol Rep 2011; 38:5065-5069.
29. el-Garf A, Salah S, Iskander I, Salah H, Amin S. MEFV mutations in Egyptian patients suffering from familial Mediterranean fever: analysis of 12 gene mutations. Rheumatol Int 2010; 30:1293-1298.
30. Cazeneuve C, Sarkisian T, Pecheux C, Dervichian M, Nedelec B, Reinert P, et al. MEFV-gene analysis in Armenian patients with familial Mediterranean fever: diagnostic value and unfavorable renal prognosis of the M694V homozygous genotype: genetic and therapeutic implications. Am J Hum Genet 1999; 65:88-97.
31. Yalcinkaya F, Cakar N, Misirhoglu M, Tumer N, Akar E, Tekin M, et al. Genotype-phenotype correlation in a large group of Turkish patients with familial Mediterranean fever: evidence for mutationindependent amyloidosis. Rheumatol 2000; 39:67-72.
32. Chaabouni H, Ksantini M, Mrad R, Kharrat M, Chaabouni M, Maazoul F, et al. MEFV mutations in Tunisian patients suffering from familial Mediterranean fever. Semin Arthritis Rheum 2007; 36:397-401.
33. Gershoni-Baruch R, Shinawi M, Leah K, Badarnah K, Brik R. Familial Mediterranean fever: prevalence, penetrance and genetic drift. Eur J Hum Genet 2001; 9:634-637.
34. Samuels J, Aksentijevich I, Torosyan Y, Centola M, Deng Z, Sood R, et al. Familial mediterranean fever at the millennium. Clinical spectrum,ancient mutations and a survey of 100 American referrals to the National Institutes of Health. Medicine (Baltimore) 1998; 77:268-297.
35. Dode C, Pecheu C, Cazeneuve C, Cattan D, Dervichian M, Goossens M. Phenotype/genotype correlations in Arab patients with FMF. Second FMF International Conference May 2000. Turkey Clin Eyp Rheumatol 2000; 18-38.
36. Ait-Idir D, Khilan A, Djerdjouri B, El-Shanti H. Spectrum of mutations and carrier frequency of familial Mediterranean fever gene in the Algerian population. Rheumatology 2011; 50:2306-2310.
37. Yepiskoposyan L, Harutyunyan A. Population genetics of familial Mediterranean fever: a review. Eur J Hum Genet 2007; 15:911-916.
38. Sabbagh A, Ghasham M, Khalek RA, Greije L, Shammaa D, Zaatari G, et al. MEFV gene mutations spectrum among Lebanese patients referred for familial Mediterranean fever work-up: experience of a major tertiary care center. Mol Biol Rep 2008; 35:447-451.
39. Ureten K, Gonulalan G, Akbal E, Gunes F, Akyurek O, Ozbek M, et al. Demographic, clinical and mutational characteristics of Turkish familial Mediterranean fever patients: results of a single center in central Anatolia. Rheumatol Int 2009; 29:1477-1480.