FMF Genotype-phenotype correlation in Iranian Azeri Turks: Association between M694V/R761H mutation and amyloidosis

Document Type : Original Article

Authors

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

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

Abstract

Objective(s):Familial Mediterranean fever (FMF), an inherited autosomal recessive disorder, is frequently present among individuals of Mediterranean origin. Differences in the clinical manifestations of FMF between different ethnic groups have been documented. The aim of the present study was to determine the most common characteristics of FMF and the relationship between clinical findings and the most common mutant alleles of the MEFV gene in an Iranian Azeri Turk population.
Materials and Methods:We analyzed clinical and genetic data from 415 patients identified as having FMF clinical symptoms and who were referred to the Molecular Genetics Laboratory of Tabriz/Iran over the last 3 years. The mutation type and clinical characteristics were determined for each patient.
Results:The following primary clinical characteristics of the patients were observed: peritonitis was observed in 378 (93.8%), high-grade fever in 351 (86.88%), arthritis in 215 (54.57%), pleuritis in 207 (53.49%), myalgia in 153 (41.69%), AA amyloidosis in 149 (40.16%), and erysipelas-like erythema in 54 (14.96%) subjects. A positive response to colchicines treatment was noted in 374 (95.1%) patients including 303 patients with two mutated alleles and 71 patients with one identified mutation.
Conclusion:In contrast to previous studies, there was no significant association between M694V mutation and development of amyloidosis. The M680I/M680I, M680I, M694I, and M694V/R761H genotypes were found to be associated with the development of amyloidosis. These results indicate that physicians need to pay careful attention to patients with asymptomatic or mildly symptomatic FMF with these genotypes.

Keywords

References

1. Brik R SM, Kepten I, Berant M, Gershoni-Baruch R. Familial Mediterranean fever: clinical and genetic characterization in a mixed pediatric population of Jewish and Arab patients. Pediatrics 1999; 103:70.
2. Touitou I. The spectrum of familial Mediterranean fever (FMF) mutations. Eur J Hum Genet 2001; 9:473-483.
3. Ozen S. Familial Mediterranean fever: revisiting an ancient disease. Eur J Pediatr 2003; 162:449-454.
4. Rawashdeh M, Majeed H. Familial Mediterranean fever in Arab children: the high prevalence and gene frequency. Eur J Pediatr 1996; 55:540-544.
5. Pras E, Aksentijevich I, Gruberg L, Balow JJ, Prosen L, Dean M, et al. Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16. N Engl J Med 1992; 326:1509-1513.
6. Pras M. Familial Mediterranean Fever: from the clinical syndrome to the cloning of the pyrin gene. . Scand J Rheumatol 1998; 27:92-97.
7. Livneh A ZD, Langevitz P, Laor A, Sohar E, Pras M Colchicine treatment of AA amyloidosis of familial Mediterranean fever: an analysis of factors aVecting outcome. Arthritis Rheum 1994; 37:1804–1811.
8. Pras E, Aksentijevich I, Levy E, Gruberg L, Prosen L, Dean M, et al. The gene causing familial Mediterranean fever maps to the short arm of chromosome 16 in Druze and Moslem Arab families. Hum Genet 1994; 94:576-577.
9. Livneh A, Langevitz P. Diagnostic and treatment concerns in familial Mediterranean fever. Baillieres Best Pract Res Clin Rheumatol 2000; 14:477-498.
10. Livneh A, Zemer D, Langevitz P, Laor A, Sohar E, Pras M. Colchicine treatment of AA amyloidosis of familial Mediterranean fever. An analysis of factors affecting outcome. Arthritis Rheum 1994; 37:1804.
11. 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.
12. Akpolat T, Ozkaya O, Ozen S. Homozygous M694V as a risk factor for amyloidosis in Turkish FMF patients. Gene 2012; 492:285-289.
13. Atagunduz M, Tuglular S, Kantarci G, Akoglu E, Direskeneli H. Association of FMF-related (MEFV) point mutations with secondary and FMF amyloidosis. Nephron Clin Pract 2004; 96:131-135.
14. Ong F, Vakil H, Xue Y, Kuo J, Shah K, Lee R, et al. The M694V mutation in Armenian-Americans: a 10-year retrospective study of MEFV mutation testing for familial Mediterranean fever at UCLA. Clin Genet 2013; 84:55-59.
15. Mansour I, Delague V, Cazeneuve C, Dode C, Chouery E, Pecheux C, et al. Familial Mediterranean fever in Lebanon: mutation spectrum, evidence for cases in Maronites, Greek orthodoxes, Greek catholics, Syriacs and Chiites and for an association between amyloidosis and M694V and M694I mutations. Europ J Hum Genet 2001; 9:51-55.
16. Shohat M, Magal N, Shohat T, Chen X, Dagan T, Mimouni A, et al. Phenotype-genotype correlation in familial Mediterranean fever: evidence for an association between met694-to-val and amyloidosis. Europ J Hum Genet 1999; 7:287-292.
17. Ben-Chetrit E. Familial Mediterranean fever (FMF) and renal AA amyloidosis--phenotype-genotype correlation, treatment and prognosis. J Nephrol 2003; 16:431-434.
18. Shinar Y, Livneh A, Langevitz P, Zaks N, Aksentijevich I, Koziol D, et al. Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever. J Rheumatol 2000; 27:1703-1707.
19. Majeed HA, El-Shanti H, Al-Khateeb MS, Rabaiha ZA. Genotype/phenotype correlations in Arab patients with familial Mediterranean fever. Semin Arthritis Rheum. 2002; 31:371-376.
20. Mattit H, Joma M, Al-Cheikh S, El-Khateeb M, Medlej-Hashim M, Salem N, et al. Familial Mediterranean fever in the Syrian population: gene mutation frequencies, carrier rates and phenotype-genotype correlation. Eur J Med Genet 2006; 49 481-486.
21. Demirkaya E, Tunca Y, Gok F, Ozen S, Gul D. A very frequent mutation and remarkable association of R761H with M694V mutations in Turkish familial Mediterranean fever patients. Clin Rheumatol 2008;27: 729-732.
22. Solak M1, Yildiz H, Koken R, Erdogan M, Eser B, Sen T, Evirgen N, Erdem S, Arikan E. Analysis of familial Mediterranean fever gene mutations in 202 patients with familial Mediterranean fever. Genet Test  2008; 3: 341-344.
23. 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.
24. Jarjour R. Familial mediterranean fever in Syrian patients: MEFV gene mutations and genotype-phenotype correlation. Mol Biol Rep 2010; 37:1-5.
25. 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.
26. 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
27. Gunesacar R, Celik MM, Arica V, Elmacioglu S, Ozturk OH. Frequency of MEFV gene mutations in Hatay province, Mediterranean region of Turkey and report of a novel missense mutation (I247V). Gene 2014;546: 195-9.

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