Birsin ÖZÇAKAR, Mesiha EKİM, Nejat AKAR, Ayşenur ÖZTÜRK

Is MEFV Gene Arg202Gln (605 G>A) a disease-causing mutation?

Amaç: Ailevi Akdeniz Ateşi (AAA) otozomal resesif kal›t›lan bir hastalıktır. Arg202Gln sık görülen bir polimorfizm olmakla birlikte G allelinin M694V ile birlikte kalıtıldığı bildirilmiştir. Bundan dolayı bu çalışmanın amacı, MEFV geni 2. ekzonda yer alan R202Q (605 G>A) mutasyonunun Türk FMF hastalarında ve kontrollerdeki dağılımını göstermektir. Yöntem ve Gereç: Çalışma, 160 FMF, 41 FMF/amiloid hastalarını ve 121 kontrolü kapsamaktadır. 10 ve 5. ekzonlar dizi analizi yöntemi ile, 2. ekzon E148Q ve R202Q mutasyonları için PCR/RFLP yöntemi ile daha önce tanımlanan tekniklere göre tüm bireyler taranmıştır. Bulgular: M694V homozigot olan 76 FMF hastasının 5’i beklenenden farklı bir haplotip taşımaktadır. 11 hastada homozigot GG alleli bulunmakta ve ikinci bir haplotipe işaret etmektedir. 121 kontrolde homozigot R202Q (605 G>A) bulunmamakta fakat 8 kontrolden 5’i (% 4,1) M694V mutasyonu için heterozigot ve R202Q ile birleşik heterozigottur. Sonuç: R202Q heterozigotluğu durumunda hastalık yapıcı etkisi görülmemektedir. Fakat hastalıkla ilişkili başka bir mutasyonla birlikteliğinde kliniğe etkisi görülmektedir. Bundan dolayı R202Q, en azından bazı FMF hastalarında, hastalığa neden olan bir mutasyon olabilir.

MEFV Arg202Gln (605 G>A) taşıma hastalık oluşturan bir mutasyon mu?

Aim: Familial Mediterranean fever (FMF) is an autosomal recessive disease. Arg202Gln was reported as a frequent polymorphism, and G allele of the mutation was in linkage disequilibrium with M694V. Thus, the aim of this study was to determine the distribution of the R202Q (605G>A) mutation in exon 2 of the MEFVgene in Turkish FMF patients and controls. Materials and Methods: The study included 160 FMF and 41 FMF/amyloid patients and 121 controls. Sequencing of exon 10 and exon 5 and PCR/RFLP analysis of E148Q and R202Q mutations of exon 2 of the MEFVgene were performed for all patients according to previously described techniques. Results: We found that 5 out of 76 M694V homozygote FMF patients carry a different haplotype from the one expected. Eleven of the patients had homozygous GG allele indicating the second haplotype. None of the 121 controls was homozygous for R202Q (605G>A), but 8 controls were heterozygous for M694V mutation and 5 (4.1%) of them were in linkage disequilibrium with R202Q. Conclusions: It seems that R202Q has no effect when it is in heterozygous state; however, when combined with another disease-causing mutation, the clinical spectrum appears. Thus, R202Q might be a disease-causing mutation at least in some of the FMF patients.

PDF

___

1. El-Shanti H, Majeed HA, El-Khateeb M. Familial Mediterranean fever in Arabs. Lancet 2006; 367(9515): 1016-24.
2. Zemer D, Pras M, Sohar E, Modan M, Cabili S, Gafni J. Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. N Engl J Med 1986; 314(16): 1001-5.
3. Turkish FMF study group. Familial Mediterranean fever in Turkey: results of a nationwide study. Medicine 2005; 84: 1-11.
4. Centola M, Aksentijevich.I, Kastner DL. The hereditary periodic fever syndromes: molecular analysis of a new family of inflammatory diseases. Hum Mol Genet 1998; 7: 1581-8.
5. http://fmf.igh.cnrs.fr/infevers/
6. Livneh A, Langevita P, Zemer D, Zaks N, Kees S, Lidar T et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 1997; 40: 1879-85.
7. Akar N, Akar E, Özel D, Tekin M, Ekim M, Yalç›nkaya F. A note on mutation analysis in familial Mediterranean fever. Pediatr Nephrol 2003; 18: 196-7.
8. Akar N, Misirlioglu M, Yalcinkaya F, Akar E, Cakar N, Tumer N et al. MEFV mutations in Turkish patients suffering from familial Mediterranean fever. Hum Mutat 2000; 15: 118-9.
9. Y›lmaz E, Ozen S, Balc› 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(7): 553-5.
10. French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet 1997; 17: 25–31.
11. International FMF Consortium. Ancient missense mutations in a new member of the Roret gene family are likely to cause familial Mediterranean fever. Cell 1997; 90: 797–807.
12. Ben-Cherit E. Familial Mediterranean fever (FMF) and renal AA amyloidosis-phenotype genotype correlation, treatment and prognosis. J Nephrol 2003; 16(3): 431-4.
13. Touitou I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet 2001; 9: 473–83.
14. Giaglis S, Papadopoulos V, Kambas K, Doumas M, Tsironidou V, Rafail S et al. MEFV alterations and population genetics analysis in a large cohort of Greek patients with familial Mediterranean fever. Clin Genet 2007; 71(5): 458-67.