Abstract
The objective of the study is to screen 12 MEFV gene mutations in Egyptian patients with familial Mediterranean fever (FMF) and to study the initial hypothesis that the phenotypic expression of the disease may be attributable to the existence of a particular mutation. We enrolled 136 Egyptian patients (74 males, and 62 females) with a clinical diagnosis of FMF. DNA was amplified by PCR and subjected to reverse hybridization for the detection of 12 MEFV gene mutations. The phenotypic expression of the disease was compared in two subgroups according to the presence of homozygote E148Q and M694V gene mutations. The most frequent gene mutations in the studied group were V726A, M694V, M680I, E148Q and M694I in 41.2, 32.4, 29.4, 25 and 20.6%, respectively. At least one of these main five founder mutations was present in 132 patients (97.1%). Thirty-two patients (23.5%) were homozygote for one of the main five founder mutations. The most common homozygote gene mutations were E148Q and M694V, each in 12 patients (8.8%). Significant increase in abdominal pain and arthritis was found in patients with homozygote M694V mutation compared to those with E148Q mutation. All patients with amyloidosis had M694V gene mutation. The increased frequency of V726A gene mutation and the rarity of amyloidosis in this study suggest that Egyptian patients may have a milder form of FMF compared to other populations. The five main founder mutations account for the vast majority of cases of FMF. M694V gene mutation may be associated with increased frequency of abdominal pain, arthritis and the presence of amyloidosis.
Similar content being viewed by others
References
Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T et al (1997) Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 40:1879–1885
Ritis K, Giaglis S, Spathari N, Micheli A, Zonios D, Tzoanopoulos D et al (2004) Non-isotopic RNase cleavage assay for mutation detection in MEFV, the gene responsible for familial Mediterranean fever, in a cohort of Greek patients. Ann Rheum Dis 63:438–443
FMF French Consortium (1997) A candidate gene for familial Mediterranean fever. Nat Genet 17:25–31
FMF International Consortium (1997) Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90:797–807
Ting JP, Kastner DL, Hoffman HM (2006) Pyrin and hereditary immunological disorders. Nat Rev Immunol 6:183–195
Mansfield E, Chae JJ, Kamaraw HD, Brat TM, Frucht DM, Askentijevich I et al (2001) The familial Mediterranean fever protein, pyrin, associates with microtubules and colocalises with actin filaments. Blood 98:851–859
Ustek D, Ekmekci CG, Selcukbiricik F, Cakiris A, Oku B, Vural B et al (2007) Association between reduced levels of MEFV messenger RNA in the peripheral blood leukocytes and acute inflammation. Arthritis Rheum 56:345–350
Shinawi M, Brik R, Berant M, Kasinetz L, Gershoni-Baruch R (2000) Familial Mediterranean fever: high gene frequency and heterogenous disease among an Israeli-Arab population. J Rheumatol 27:1492–1495
Gershoni-Baruch R, Shinawi M, Kasinetz L, Badarna K, Brik R (2001) Familial Mediterranean fever: prevalence, penetrance and genetic drift. Eur J Hum Genet 9:634–637
Dode C, Pecheux C, Cazeneuve C, Cattan D, Dervichian M, Goossens M et al (2000) Mutations in the MEFV gene in a large series of patients with clinical diagnosis of familial Mediterranean fever. Am J Med Genet 92:241–246
Centola M, Kastner D, International FMF Consortium (1997) Cloning of MEVF: implications for the pathophysiology of familial Mediterranean fever. In: Sohar E, Gafni J, Pras M (eds) Familial Mediterranean fever. Freund, London, pp 252–259
Yalcinkaya F, Cakar N, Misirllioglu N, Tumer N, Akar N, Tekin M et al (2000) Genotype–phenotype correlation in a large group of Turkish patients with familial Mediterranean fever: evidence of mutation-independent amyloidosis. Rheumatology 39:67–72
Yilmaz E, Ozen S, Balci B, Duzava A, Topaloglu R, Besbas N et al (2001) Mutation frequency of familial Mediterranean fever and evidence for a high carrier rate in the Turkish population. Eur J Hum Genet 9:553–555
Belmahi L, Sefiani A, Feingold J, Delpech M, Grateau G, Dode C (2006) Prevalence and distribution of MEFV mutations among Arabs from the Maghreb patients suffering from familial Mediterranean fever. C R Biol 329(2):71–74
Mattit H, Joma M, Al-Cheikh S, El-Khateeb M, Medlej-Hashim M, Salem N et al (2006) Familial Mediterranean fever in the Syrian population: gene mutation frequencies, carrier rates and phenotype–genotype correlation. Eur J Med Genet 49:481–486
Kone Paut I, Dubuc M, Sportouch J, Minodier P, Garnier JM, Touitou I (2000) Phenotype–genotype correlation in 91 patients with familial Mediterranean fever reveals a high frequency of cutaneomucous features. Rheumatology (Oxf) 39:1275–1279
Shinar Y, Livneh A, Langevitz P, Zaks N, Aksentijevich I, Koziol DE et al (2000) Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever. J Rheumatol 27:1703
Kogan A, Shinar Y, Lidar M, Revivo A, Langevit P, Padeh S et al (2001) Common MEFV mutations among Jewish ethnic groups in Israel: high frequency of carrier and phenotype II states and absence of a perceptible biological advantage for carrier state. Am J Med Genet 102:272–276
Yalcinkaya F, Topaloglu R, Yimaz E, Emre S, Erken E, on behalf of the Turkish FMF Study Group (2002) Distribution of MEFV mutations and phenotype genotype analysis in Turkish patients with FMF: a national wide study. Clin Exp Rheumatol 20(Suppl 26):S90 (abstract)
Medlej-Hashim M, Delague V, Chouery E, Salem N, Rawashdeh M, Lefranc G et al (2004) Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects. BMC Med Genet 5(1):4
Ben Chetrit E, Backenroth R (2001) Amyloidosis induced end stage renal disease in patients with familial Mediterranean fever is highly associated with point mutations in the MEFV gene. Ann Rheum Dis 60:146–149
Gershoni-Baruch R, Brik R, Zacks N, Shinawi M, Lidar M, Livneh A (2003) The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever. Arthritis Rheum 48:1149–1155
Akar S, Soytruk M, Onen F, Tunca M (2003) Serum amyloid A1 and tumor necrosis factor-alpha alleles in Turkish familial Mediterranean fever patients with and without amyloidosis. Amyloid 10:12–16
Delibas A, Oner A, Balci B, Demircin G, Bulbul M, Bek K et al (2005) Genetic risk factors of amyloidogenesis in familial Mediterranean fever. Am J Nephrol 25(5):434–440
Pras E, Langevitz P, Livneh A et al (1997) Genotype–phenotype correlation in familial Mediterranean fever (a preliminary report). In: Sohar E, Gafni J, Pras M (eds) Familial Mediterranean fever. Freund, London, pp 260–264
Yalcinkaya F, Akar N, Misirlioglu M (1998) Familial Mediterranean fever: amyloidosis and the V725A mutation. N Engl J Med 338:993–994
Dewalle M, Domingo C, Rozenbaum M, Ben-Chetrit E, Cattan D, Bernot A et al (1998) Phenotype–genotype correlation in Jewish patients suffering from familial Mediterranean fever (FMF). Eur J Hum Genet 6:95–97
Livneh A, Langevitz P, Shinar Y, Zaks N, Kastner DL, Pras M et al (1999) MEFV mutation analysis in patients suffering from amyloidosis of familial Mediterranean fever. Amyloid 6:1–6
Shohat M, Magal N, Shohat T, Chen X, Dagan T, Mimouni A et al (1999) Phenotype–genotype correlation in familial Mediterranean fever: evidence for an association between M694V and amyloidosis. Eur J Hum Genet 7:287–292
Mimouni A, Magal N, Stoffman N, Shohat T, Minasian A, Krasnov M et al (2000) Familial Mediterranean fever: effects of genotype and ethnicity on inflammatory attacks and amyloidosis. Pediatrics 105(5):1150–1151 (abstract)
Ben-Chetrit E, Lerer I, Malamud E, Damingo C, Abeliavich D (2000) The E148Q mutation in MEFV gene: is it a disease causing mutation or a sequence variant? Hum Mutat 15:285–286
Booth DR, Lachmann HJ, Gillmore JD, Booth SE, Hawkins PN (2001) Prevalence and significance of the familial Mediterranean fever gene mutation encoding pyrin Q148. QJM 94:527–531
Tchernitchko D, Legendre M, Cazeneuve C, Delahaye A, Neil F, Amselen S (2003) The E148Q MEFV allele is not implicated in the development of familial Mediterranean fever. Hum Mutat 22:239–240
Ozen S, Besbas N, Bakkaloglu A, Yilmaz E (2002) Pyrin Q148 mutation and familial Mediterranean fever. QJM 95:332–333
Topaloglu R, Ozaltin F, Yilmaz E, Ozen S, Balci B, Besbas N et al (2005) E148Q is a disease causing MEFV mutation: a phenotypic evaluation in patients with familial Mediterranean fever. Ann Rheum Dis 64:750–752
Solak M, Yildiz H, Koken R, Erdogan M, Eser B, Sen T et al (2008) Analysis of familial Mediterranean fever gene mutations in 202 patients with familial Mediterranean fever. Genet Test 3:341–344
Acknowledgments
Approval from the Research Ethics Committee, Faculty of Medicine, Cairo University, was not necessary because gene mutation analysis was done as a part of the usual care to confirm the diagnosis. All parents signed a written informed consent.
Conflict of interest statement
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
El-Garf, A., Salah, S., Iskander, I. et al. MEFV mutations in Egyptian patients suffering from familial Mediterranean fever: analysis of 12 gene mutations. Rheumatol Int 30, 1293–1298 (2010). https://doi.org/10.1007/s00296-009-1140-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00296-009-1140-z