The Egyptian Journal of Haematology

: 2014  |  Volume : 39  |  Issue : 2  |  Page : 64--67

Study of MEFV gene R202Q polymorphism in Egyptian patients with familial Mediterranean fever

Lobna O ElMessery1, Hala F Elhagrasy2,  
1 Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
2 Department of Pediatrics, Suez Canal University, Ismailia, Egypt

Correspondence Address:
Lobna O ElMessery
Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo 11399


Familial Mediterranean fever (FMF) is a hereditary disorder characterized by recurrent attacks of fever and serositis. Several mutations in the MEFV gene have been associated with the disease. The aim of the present study is to investigate the frequency of the R202Q(605G>A) polymorphism in exon 2 of the MEFV gene and its clinical significance in a cohort of Egyptian patients with FMF. The study included 55 FMF patients and 40 healthy controls. The polymorphism was tested using polymerase chain reaction (PCR) based restriction fragment length polymorphism (RFLP). The genotype and allele frequency was similar in patients and controls. No significant association was found between demographic and clinical characteristics of patients and R202Q genotype. Further studies covering wider geographical areas in Egypt are required to reveal the diagnostic relevance of this molecular marker in Egypt.

How to cite this article:
ElMessery LO, Elhagrasy HF. Study of MEFV gene R202Q polymorphism in Egyptian patients with familial Mediterranean fever .Egypt J Haematol 2014;39:64-67

How to cite this URL:
ElMessery LO, Elhagrasy HF. Study of MEFV gene R202Q polymorphism in Egyptian patients with familial Mediterranean fever . Egypt J Haematol [serial online] 2014 [cited 2020 Jan 26 ];39:64-67
Available from:

Full Text


Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent episodes of fever and inflammation in the peritoneum, synovium or pleura accompanied by pain [1] . Destructive oligoarthropathy and potentially life-threatening secondary amyloidosis are the major long-term complications of the disease [2] . The disease is mostly prevalent in people from the Mediterranean basin, including Sephardic Jews, Turks, Arabs, and Armenians [3] .

Mediterranean fever gene (MEFV) has already been identified as being responsible for FMF. It is located on the short arm of chromosome 16p13.3 and includes 10 exons [4] . It encodes a 781 amino acids protein called marenostrin or pyrin, which is expressed only in the neutrophils and monocytes, the cell types involved in innate immune response. Pyrin has a key role in the regulation of inflammasome activity and prointerleukin 1b processing [5] . Mutations of the MEFV gene diminish pyrin expression, which abolish its inhibitory effect on caspase 1-mediated activation of interleukin 1b leading to uncontrolled inflammation [6] . At present, more than 180 gene polymorphisms, primarily clustered in exon 10, have been identified in affected patients. Of these mutations, five account for more than 70% of FMF cases - V726A, M694V, M694I, M680I, and E148Q - and have different frequencies in classically affected populations [2] .

The association between FMF and some MEFV gene mutations has been clearly established [7] . However, controversy exists regarding the role of some amino acid substitutions, namely R202Q where glutamine (Q) substitutes for arginine (R) [8] . It was demonstrated that R202Q polymorphism (605G>A) might be a disease-causing mutation in some FMF patients [9] .

The aim of the present study was to investigate the frequency of R202Q polymorphism of the MEFV gene in Egyptian FMF patients and its diagnostic relevance.

 Patients and methods


The present study was conducted on 55 unrelated patients with FMF, 31 (56.3%) male patients and 24 (43.6%) female patients with a mean age of 12.9 ± 4.2 years ranging from 8 to 18 years, and on 40 unrelated age-matched and sex-matched healthy controls. All patients were diagnosed according to the Tel Hashomer criteria [10] . They were referred to molecular diagnostic unit in Children Hospital, Cairo University, for genotyping. All patients were treated with colchicine. All participants, patients and healthy controls, were of Egyptian origin.

Polymerase chain reaction-restriction fragment length polymorphism

Genomic DNA was extracted from EDTA blood samples using commercial DNA isolation kit (Axygen Biosciences, Central Avenue, Union City, USA), according to manufacturer's instructions. Isolated DNA was stored at -20°C until use for PCR amplification. The R202Q (605G>A) polymorphism of MEFV exon 2 was tested by means of PCR-based restriction fragment length polymorphism as previously described [7] using primers, F: 5'-ATG TTG GGC CCT AAA CGT GG-3' and R: 5'-TCC TTC AGG TCC GCA GAT GC-3'. The PCR reaction was carried out in the DNA thermal cycler (PTC Programmable Thermal Controller; MJ Research, Watertown, Massachusetts, USA). The computerized thermal cycler was programmed for the following conditions: an initial denaturation at 95°C for 5 min followed by 35 cycles of denaturation at 95°C (15 s), annealing at 58°C (30 s), and extension at 72°C (3 min), with a final 10 min extension at 72°C. The G→A transition at codon 202 created a PvuII site, which replaced a 566 bp fragment with two fragments of 196 and 370 bp. PvuII-treated PCR products were detected by electrophoresis on 2% agarose gel, stained with ethidium bromide and examined under UV light.

Statistical analysis

Quantitative data were presented as mean ± SD and qualitative data as number and frequency. The χ2 and Fisher's exact tests were used to compare categorical data using SPSS (15.0; SPSS Inc., Chicago, Illinois, USA). A P value of less than 0.05 was considered significant.


The demographic and clinical data of patients are shown in [Table 1]. The frequency of R202Q polymorphism was 32.7 and 22.5% in patients and controls, respectively. The genotype and allele distribution of R202Q polymorphism are shown in [Table 2]. No statistically significant difference was found between patients and controls regarding genotype and allele frequency (P = 0.35 and 0.30, respectively). No statistically significant association was found between R202Q polymorphism and clinical and demographic features of patients, such as age, sex, age at disease onset, age at diagnosis, fever, abdominal pain, arthritis, pleurisy, erythema, response to colchicine, family history, and appendectomy (data not shown).{Table 1}{Table 2}


The diagnosis of FMF has been for long based on the clinical features and exclusion of other causes of periodic fever, thus making it difficult to establish a correct diagnosis in patients with milder or atypical manifestations of the disease [11] . The demonstration of the MEFV gene mutations is necessary to establish a definite diagnosis in suspected cases [1] . Several studies have been published, involving the frequency of the five most common identified MEFV gene mutations namely M694I, V726A, M680I, E148Q, and M694V in Egyptian FMF patients [12],[13],[14],[15] . The frequency of the detected mutations was not consistent among different studies and none of the studied mutations could be identified as being the most prevalent in Egyptian FMF patients, reflecting the heterogeneity of the population and the heterogeneous origin of FMF in Egypt [15] . This mutational heterogeneity appears to be less obvious among other ethnic populations. M694V mutation was found in 97% of the North African Jews in Israel [16] , whereas M694I mutation was present in 80% of Algerian Arabs [17] . In a study from Turkey, M694V was reported to be the most common MEFV mutation constituting 57.0% of mutations detected [18] . MEFV gene mutations could not be characterized in almost 40% of enrolled FMF cases in some Egyptian studies [13],[15] . This raised the possibility of other MEFV mutations as being responsible for the disease.

R202Q polymorphism has previously been reported as a common polymorphism [9] ; however, its clinical significance is still under investigation. In the present study, we investigated the R202Q polymorphism in 55 FMF patients and 40 healthy controls. R202Q polymorphism was found in 32.7% of FMF patients and 22.5% of the controls. In a Turkish study, the frequency was reported to be 57.5 and 44.7% in patients and controls, respectively [8] .

The frequency of heterozygosity did not significantly differ in patients compared with controls. In a study conducted on Turkish FMF patients, heterozygosity was also similar in both patients and controls but homozygosity for R202Q was significantly higher in patients than in controls, suggesting that this polymorphism may not have a disease effect in heterozygous state but can be a cause of illness in the homozygous form [8] . In another Turkish study, R202Q polymorphism was present in the control group only in the heterozygous form but was found in the homozygous form in two FMF patients with uncharacterized mutations who developed amyloidosis, again suspecting its role as a disease-causing mutation in the homozygous form [9] . In one study from Greece, R202Q homozygosity was found in 12 of the 25 (48%) cases of FMF in whom no other MEFV mutation could be characterized [19] , further supporting the hypothesis that R202Q polymorphism may have a diagnostic relevance in the homozygous state. In our study, only one patient was homozygous for R202Q polymorphism and none of the controls was; however, we could not draw an inference due to the low incidence of homozygosity in the study groups. R202Q polymorphism has also been associated with rare FMF causative mutations in Mediterranean populations [20] . In addition, R202Q polymorphism was detected along with other MEFV mutations in Turkish patients with fibromyalgia, the clinical features of which show some overlapping symptoms with FMF [21] .

R202Q polymorphism was found in linkage disequilibrium with M694V [9] , which is reported to be the most prevalent MEFV mutation in Turkish FMF patients [18] . Homozygous state for R202Q polymorphism was found in 50% of M694V heterozygous mutants and 88.8% M694V homozygous mutants [9] . The frequency of M694V in Egyptian FMF patients was not consistent among published studies. It was not detected in one study [15] , detected in only 7.8% [13] , and reached up to 32.4% in another study [12] . This may explain the lower frequency of R202Q detected in our study.

It was reported that R202Q polymorphism causes a mild change in electrochemical energy of the whole pyrin molecule, but still its functional effect remains unclear [8] .

In our study, R202Q polymorphism could not be associated with FMF. However, proven of diagnostic value in other ethnic groups, extended studies covering wider geographical areas in Egypt are required to elucidate the diagnostic relevance of this polymorphism in Egyptian patients.



1Onen F. Familial Mediterranean fever. Rheumatol Int 2006; 26 :489-496.
2Yepiskoposyan L, Harutyunyan A. Population genetics of familial Mediterranean fever: a review. Eur J Hum Genet 2007; 15 :911-916.
3Ben Chetrit E, Touitou E. Familial Mediterranean fever in the world. Arthritis Rheum 2009; 6 :1447-1453.
4Pras E, Aksentijevich J, Gruberq L, Balaw GE, Procen L, Dean M, et al. Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome16. N Engl J Med 1992; 326 :1509-1513.
5Papin S, Cuenin S, Aqostini L, Martinon F, Werner F, Beer HD, et al. The SPRY domain of pyrin mutated in familial Mediterranean fever patients interacts with inflammasome components and inhibits proIL1 beta processing. Cell Death Differ 2007; 14 :1457-1466.
6Yilmaz 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.
7Bernot A, Da Silva C, Petit J, Cruaud C, Caloustian C, Castet V, et al. Non founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever. Hum Mol Genet 1998; 7 :1317-1325.
8Yigit S, Karakus N, Tasyurit T, Kaya SU, Bozkurt N, Kisacik B. Significance of MEFV gene R202Q polymorphism in Turkish familial Mediterranean fever patients. Gene 2012; 506 :43-45.
9Otzurk A, Ozcakar B, Ekim M, et al. Is MEFV gene Arg202Gln(605 G>A) a disease causing mutation? Turk J Med Sci 2008; 38 :204-208.
10Livneh A, Lanqevitz P, Zemer D, Zaks N, Kees S, Lidar T, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 1997; 40 :1879-1885.
11Ritis K, Giaglis S, Spathari N, Micheli A, Zonios D, Tzoanopoulos D, et al. Non isotopic RNA cleavage assay for mutation detection in MEFV, the gene responsible for familial Mediterranean fever in a cohort of Greek patients. Ann Rheum Dis 2004; 63 :438-443.
12El-Garf A, Salah S, Iskander I, Salah H, Amin SN. MEFV mutations in Egyptian patients suffering from familial Mediterranean fever: analysis of 12 gene mutations. Rheumatol Int 2010; 30 :1293-1298.
13El Gezery D,Abou Zeid A Hashad D, El-Sayegh HK. MEFV gene mutations in Egyptian patients with familial Mediterranean fever. Genet Test Mol Biomarkers 2010; 14 :263-268.
14Talaat H, Mohamed M, El Rifai N, Gomaa MA. The expanded clinical profile and the efficacy of colchicine therapy in Egyptian children suffering from familial Mediterranean fever: a descriptive study. Ital J Pediatr 2012; 38 :66.
15Ibrahim G, Khalil F, Mostafa F, et al. Analysis of common MEFV mutations in Egyptian patients with familial Mediterranean fever: molecular characterization of the disease. Br J Biomed Sci 2010; 67 :202-207.
16Centola M, Kastner D. Familial Mediterranean fever. In: Sohar E, Gafni J, Pras M, editors. International FMF Consortium: Cloning of MEVF: implications for the pathophysiology of familial Mediterranean fever. London: Freund; 1997. 252-259.
17Belmahi 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.
18Tunca M, Akar S, Onen F, Ozdogan H, Kasapcopur O, Yalcinkaya F. Turkish FMF Study Group. Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore) 2005; 84 :1-11.
19Giaglis S, Papdopoulos V, Kambas K, Doumas M, Tsironidou V, Rafail S, et al. MEFV alterations and population genetics analysis in alarge cohort of Greek patients with familial Mediterranean fever. Clin Genet 2007; 71 :458-467.
20Aldea A1, Calafell F, Aróstegui JI, 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 MRFV locus. Hum Mut ■; 2004; 23 :399.
21Karakus N, Yigit S, Inanir A, Inanir S, Toprak H, Okan S. Association between sequence variations of the Mediterranean fever gene and fibromyalgia in a cohort of Turkish patients. Clin Chim Acta 2012; 414 :36-40.