Abstract
Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder caused by mutations in the MEFV gene. The disease is especially common among Armenian, Turkish, Jewish and Middle East Arab populations. To identify the frequency and the spectrum of common MEFV mutations in different Iranian populations, we investigated a cohort of 208 unselected asymptomatic individuals and 743 FMF patients. Nine hundred and fifty-one samples were analysed for the presence of 12 MEFV mutations by PCR and reverse-hybridization (FMF StripAssay, ViennaLab, Vienna, Austria). Confirmatory dideoxy sequencing of all MEFV gene exons was performed for 39 patients. Fifty-seven (27.4%) healthy individual carried mutant MEFV alleles. Three hundred and ninety-one (52.6%) FMF patients were found positive for either one (172/743; 23.1%), two or three MEFV mutations. Using dideoxy sequencing, three novel variants, A66P, R202W and H300Q, could be identified. Our analysis revealed an allele frequency and carrier rate of 15.6 and 27.4%, respectively, among healthy Iranians. Still moderate compared to neighbouring Armenia, but higher than in Turkey or Iraq, these data suggest that FMF is remarkably common among Iranian populations. E148Q was most frequent in the group of healthy individuals, whereas M694V was the most common mutation among FMF patients, thereby corroborating previous studies on MEFV mutational spectra in the Middle East. Accordingly, MEFV mutations are frequent in healthy Iranian individuals across different ethnic groups. Based on this finding, the awareness for FMF and the implementation of augmented carrier screening programmes considering the multiethnic nature of the Iranian population should be promoted.
Similar content being viewed by others
References
Akar N., Akar E. and Yalcinkaya F. 2001 E148Q of the MEFV gene causes amyloidosis in familial Mediterranean fever patients. Pediatrics 108, 215.
Akin H., Onay H., Turker E., Cogulu O. and Ozkinay F. 2010 MEFV mutations in patients with familial Mediterranean fever from the Aegean region of Turkey. Mol. Biol. Rep. 37, 93–98.
Al-Alami J. R., Tayeh M. K., Najib D. A., Abu-Rubaiha Z. A., Majeed H. A., Al-Khateeb M. S. et al. 2003 Familial Mediterranean fever mutation frequencies and carrier rates among a mixed Arabic population. Saudi Med. J. 24, 1055–1059.
Bernot A., da Silva C., Petit J. L., Cruaud C., Caloustian C., Castet V. et al. 1998 Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF). Hum. Mol. Genet. 7, 1317–1325.
Bidari A., Ghavidel-Parsa B., Najmabadi H., Talachian E., Haghighat-Shoar M., Broumand B. et al. 2010 Common MEFV mutation analysis in 36 Iranian patients with familial Mediterranean fever: clinical and demographic significance. Mod. Rheumatol. 20, 566–572.
Bonyadi M., Esmaeili M., Jalali H., Somi M. H., Ghaffari A., Rafeey M. et al. 2009 MEFV mutations in Iranian Azeri Turkish patients with familial Mediterranean fever. Clin. Genet. 76, 477–480.
Bonyadi M., Esmaeili M., Karimi A. and Dastgiri S. 2010 Common Mediterranean fever gene mutations in the Azeri Turkish population of Iran. Genet. Test. Mol. Biomarkers 14, 149–151.
Booth D. R., Gillmore J. D., Lachmann H. J., Booth S. E., Bybee A., Soyturk M. et al. 2000 The genetic basis of autosomal dominant familial Mediterranean fever. QJM 93, 217–221.
Booth D. R., Lachmann H. J., Gillmore J. D., Booth S. E. and Hawkins P. N. 2001 Prevalence and significance of the familial Mediterranean fever gene mutation encoding pyrin Q148. QJM 94, 527–531.
Booty M. G., Chae J. J., Masters S. L., Remmers E. F., Barham B., Le J. M. et al. 2009 Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum. 60, 1851–1861.
Cazeneuve C., Sarkisian T., Pêcheux C., Dervichian M., Nédelec B., Reinert P. et al. 1999 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. 65, 88–97.
Comak E., Akman S., Koyun M., Dogan C. S., Gokceoglu A. U., Arikan Y. et al. 2014 Clinical evaluation of R202Q alteration of MEFV genes in Turkish children. Clin. Rheumatol. 33, 1765–1771.
Dogan H. O., Koca Y., Erden G., Karaaslan Y. and Bozat H. 2012 Evaluating MEFV mutation frequency in Turkish familial Mediterranean fever suspected patients and gender correlation: a retrospective study. Mol. Biol. Rep. 39, 6193–6196.
Ece A., Cakmak E., Uluca U., Kelekci S., Yolbas I., Gunes A. et al. 2014 The MEFV mutations and their clinical correlations in children with familial Mediterranean fever in southeast Turkey. Rheumatol. Int. 34, 207–212.
el-Garf A., Salah S., Iskander I., Salah H. and Amin S. N. 2010 MEFV mutations in Egyptian patients suffering from familial Mediterranean fever: analysis of 12 gene mutations. Rheumatol. Int. 30, 1293–1298.
El Gezery D. A., Abou-Zeid A. A., Hashad D. I. and El-Sayegh H. K. 2010 MEFV gene mutations in Egyptian patients with familial Mediterranean fever. Genet. Test. Mol. Biomarkers 14, 263–268.
Esmaeili M., Bonyadi M., Rafeey M., Sakha K. and Somi M. H. 2008 Common MEFV mutation analysis in Iranian Azeri Turkish patients with familial Mediterranean fever. Semin. Arthritis Rheum. 37, 334–338.
Gershoni-Baruch R., Brik R., Shinawi M. and Livneh A. 2002 The differential contribution of MEFV mutant alleles to the clinical profile of familial Mediterranean fever. Eur. J. Hum. Genet. 10, 145–149.
Gunesacar R., Celik M. M., Arica V., Elmacioglu S. and Ozturk O. H. 2014 Frequency of MEFV gene mutations in Hatay province, Mediterranean region of Turkey and report of a novel missense mutation (I247V). Gene 546, 195–199.
Ibrahim G. H., Khalil F. A., Mostafa F., Fawzy M. S., Said M., Omar A. E. et al. 2010 Analysis of common MEFV mutations in Egyptian patients with familial Mediterranean fever: molecular characterisation of the disease. Br. J. Biomed. Sci. 67, 202–207.
Jabbarpour Bonyadi M., Mir Najd Gerami S., Somi M. and Dastgiri S. 2015 MEFV mutations in northwest of Iran: a cross sectional study. Iran J. Basic Med. Sci. 18, 53–57.
Jarjour R. A. 2010 Familial Mediterranean fever in Syrian patients: MEFV gene mutations and genotype–phenotype correlation. Mol. Biol. Rep. 37, 1–5.
Kishida D., Nakamura A., Yazaki M., Tsuchiya-Suzuki A. , Matsuda M. and Ikeda S. 2014 Genotype–phenotype correlation in Japanese patients with familial Mediterranean fever: differences in genotype and clinical features between Japanese and Mediterranean populations. Arthritis Res. Ther. 16, 439–449.
La Regina M., Nucera G., Diaco M., Procopio A., Gasbarrini G., Notarnicola C. et al. 2003 Familial Mediterranean fever is no longer a rare disease in Italy. Eur. J. Hum. Genet. 11(1), 50–56.
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.
Magal N., Lotan R., Allon Shalev S., Khanaysi N. and Shohat M. 1998 New hot spot in the gene causing familial Mediterranean fever. Am. J. Hum. Genet. 63, A2155.
Majeed H. A., El-Khateeb M., El-Shanti H., Rabaiha Z. A., Tayeh M. and Najib D. 2005 The spectrum of familial Mediterranean fever gene mutations in Arabs: report of a large series. Semin. Arthritis Rheum. 34, 813–818.
Mansour I., Delague V., Cazeneuve C., Dode C., Chouery E., Pecheux C. et al. 2001 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. Eur. J. Hum. Genet. 9, 51–55.
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.
Medlej-Hashim M., Rawashdeh M., Chouery E., Mansour I., Delague V., Lefranc G. et al. 2000 Genetic screening of fourteen mutations in Jordanian familial Mediterranean fever patients. Hum. Mutat. 15, 384.
Miller S., Dykes D. and Polesky H. 1988 A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 16, 1215.
Mohammadnejad L. and Farajnia S. 2013 Mediterranean fever gene analysis in the Azeri Turk population with familial Mediterranean fever: evidence for new mutations associated with disease. Cell Journal (Yakhteh) 15, 152–159.
Najmabadi H., Karimi-Nejad R., Sahebjam S., Pourfarzad F., Teimourian S., Sahebjam F. et al. 2001 The β-thalassemia mutation spectrum in the Iranian population. Hemoglobin 25, 285–296.
Najmabadi H., Neishabury M., Sahebjam F., Kahrizi K., Shafaghati Y., Nikzat N. et al. 2003 The Iranian human mutation gene bank: a data and sample resource for worldwide collaborative genetics research. Hum. Mutat. 21, 146–150.
Ozdemir O., Sezgin I., Kurtulgan H. K., Candan F., Koksal B., Sumer H. et al. 2011 Prevalence of known mutations in the MEFV gene in a population screening with high rate of carriers. Mol. Biol. Rep. 38, 3195–3200.
Padeh S., Shinar Y., Pras E., Zemer D., Langevitz P., Pras M. et al. 2003 Clinical and diagnostic value of genetic testing in 216 Israeli children with familial Mediterranean fever. J. Rheumatol. 30, 185–190.
Papadopoulos V. P., Giaglis S., Mitroulis I. and Ritis K. 2008 The population genetics of familial Mediterranean fever: a meta-analysis study. Ann. Hum. Genet. 72, 752–761.
Papadopoulos V., Mitroulis I. and Giaglis S. 2010 MEFV heterogeneity in Turkish familial Mediterranean fever patients. Mol. Biol. Rep. 37, 355–358.
Pras E., Aksentijevich I., Gruberg L., Balow J. E. Jr., Prosen L., Dean M. et al. 1992 Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16. N. Engl. J. Med. 326, 1509–1513.
Sabokbar T., Malayeri A., Azimi C., Raeeskarami S., Ziaee V., Aghighi Y. et al. 2014 Spectrum of mutations of familial Mediterranean fever gene in Iranian population. Ann. Paediatr. Rheum. 3, 11–17.
Salehzadeh F., Jafari Asl M., Hosseini Asl S., Jahangiri S. and Habibzadeh S. 2015 MEFV gene profile in northwest of Iran, twelve common MEFV gene mutations analysis in 216 patients with familial Mediterranean fever. Iran J. Med. Sci. 40, 68–72.
Sediva A., Horvath R., Manasek V., Gregorova A., Plevova P., Horackova M. et al. 2014 Cluster of patients with familial Mediterranean fever and heterozygous carriers of mutations in MEFV gene in the Czech Republic. Clin. Genet. 86, 564–569.
Sohar E., Gafni J., Pras M. and Heller H. 1967 Familial Mediterranean fever: a survey of 470 cases and review of the literature. Am. J. Med. 43, 227–253.
Tchernitchko D., Legendre M., Cazeneuve C., Delahaye A., Niel F. and Amselem S. 2003 The E148Q MEFV allele is not implicated in the development of familial Mediterranean fever. Hum. Mutat. 22, 339–340.
Toplak N., Dolezalova P., Constantin T., Sediva A., Pasic S., Ciznar P. et al. 2010 Periodic fever syndromes in eastern and central European countries: results of a pediatric multinational survey. Pediatr. Rheumatol. Online J. 8, 29–34.
Touitou I. 2001 The spectrum of familial Mediterranean fever (FMF) mutations. Eur. J. Hum. Genet. 9, 473–483.
Tunca M., Akar S., Hawkins P. N., Booth S. E., Sengul B., Yavuzsen T. U. et al. 2002 The significance of paired MEFV mutations in individuals without symptoms of familial Mediterranean fever. Eur. J. Hum. Genet. 10, 786–789.
Tunca M., Akar S., Onen F., Ozdogan H., Kasapcopur O. , Yalcinkaya F. et al. 2005 Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore) 84, 1–11.
Yalcinkaya F., Cakar N., Misirlioglu M., Tumer N., Akar N., Tekin M. et al. 2000 Genotype–phenotype correlation in a large group of Turkish patients with familial mediterranean fever: evidence for mutation-independent amyloidosis. Rheumatology (Oxford) 39, 67–72.
Yilmaz E., Ozen S., Balci B., Duzova 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.
Acknowledgement
We thank the Iranian FMF patients, their clinicians and healthy individuals for their consent and contributions.
Author information
Authors and Affiliations
Corresponding authors
Additional information
[Beheshtian M., Izadi N., Kriegshauser G., Kahrizi K., Parsi Mehr E., Rostami M., Hosseini M., Azad M., Montajabiniat M., Kariminejad A., Nemeth S., Oberkanins C. and Najmabadi H. 2016 Prevalence of common MEFV mutations and carrier frequencies in a large cohort of Iranian populations. J. Genet. 95, xx–xx]
Appendix
Appendix
Rights and permissions
About this article
Cite this article
BEHESHTIAN, M., IZADI, N., KRIEGSHAUSER, G. et al. Prevalence of common MEFV mutations and carrier frequencies in a large cohort of Iranian populations. J Genet 95, 667–674 (2016). https://doi.org/10.1007/s12041-016-0682-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12041-016-0682-6