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Mediterranean Fever gene analysis in the azeri turk population with familial mediterranean Fever: evidence for new mutations associated with disease.

ABSTRACT: OBJECTIVE:Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent febrile attacks accompanied by serosal and synovial membrane inflammation. FMF is caused by mutations in the MEFV gene and are found usually among Mediterranean populations, Armenians, Turks, Arabs and Jews. The aim of this study was to determine the frequency of MEFV gene mutations among FMF patients in the Azeri Turk population in North-West of Iran. MATERIALS AND METHODS:In this descriptive study, 130 FMF patients with Azeri Turk origin were screened for mutations in four exons (2, 3, 5 and10) of MEFV gene. Genomic DNA was extracted from whole blood and entered in ARMS-PCR and PCR-RFLP reactions. When cases were negative in ARMS-PCR and PCR-RFLP, the exons were amplified and subjected to direct sequencing. RESULTS:Our results showed that the most common mutations in this study population was M694V (40.19%) followed by E148Q (17.64%), V726A (13.72%), M680I (12.74%) and M694I (2.94%) mutations. Four new mutations including K618N, K716M, S614F and G136E were identified in our study. CONCLUSION:The prevalence of five common mutations in our study was highly similar to previous studies analysing the Mediterranean basin populations. Investigation by sequencing also revealed four new variants in the study population. The main genotypephenotype correlation finding was the presence of M694V mutation in homozygote or compound heterozygote state in the patients with renal manifestations.

SUBMITTER: Mohammadnejad L

PROVIDER: S-EPMC3712776 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Mediterranean Fever gene analysis in the azeri turk population with familial mediterranean Fever: evidence for new mutations associated with disease.

Mohammadnejad Leila L Farajnia Safar S

Cell journal 20130702 2

<h4>Objective</h4>Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent febrile attacks accompanied by serosal and synovial membrane inflammation. FMF is caused by mutations in the MEFV gene and are found usually among Mediterranean populations, Armenians, Turks, Arabs and Jews. The aim of this study was to determine the frequency of MEFV gene mutations among FMF patients in the Azeri Turk population in North-West of Iran.<h4>Materials and methods</h4>I ...[more]

PMID: 23862117

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Project description:Familial Mediterranean fever (FMF) is caused by mutations within the Mediterranean fever (MEFV) gene. Disease severity depends on genotype and gene dose with most serious clinical courses observed in patients with M694V homozygosity. Neutrophils are thought to play an important role in the initiation and perpetuation of inflammatory processes in FMF, but little is known about the specific characteristics of these cells in FMF patients. To further characterize neutrophilic inflammatory responses in FMF and to delineate gene-dose effects on a cellular level, we analyzed cytokine production and activation levels of isolated neutrophils derived from patients and subjects with distinct MEFV genotypes, as well as healthy and disease controls. Serum levels of interleukin-18 (IL-18) (median 11,485 pg/ml), S100A12 (median 9,726 ng/ml), and caspase-1 (median 394 pg/ml) were significantly increased in patients with homozygous M694V mutations. Spontaneous release of S100A12, caspase-1, proteinase 3, and myeloperoxidase (MPO) was restricted to ex vivo cultured neutrophils derived from patients with two pathogenic MEFV mutations. IL-18 secretion was highest in patients with two mutations but also increased in neutrophils from healthy heterozygous MEFV mutation carriers, exhibiting an ex vivo gene-dose effect, which was formerly described by us in patients' serum. CD62L (l-selectin) was spontaneously shed from the surface of ex vivo cultured neutrophils [median of geometric mean fluorescence intensity (gMFI) after 5 h: 28.8% of the initial level]. While neutrophils derived from healthy heterozygous mutation carriers again showed a gene-dose effect (median gMFI: 67.1%), healthy and disease controls had significant lower shedding rates (median gMFI: 83.6 and 82.9%, respectively). Co-culture with colchicine and/or stimulation with adenosine triphosphate (ATP) and lipopolysaccharide (LPS) led to a significant increase in receptor shedding. Neutrophils were not prevented from spontaneous shedding by blocking IL-1 or the NLRP3 inflammasome. In summary, the data demonstrate that ex vivo cultured neutrophils derived from FMF patients display a unique phenotype with spontaneous release of high amounts of IL-18, S100A12, MPO, caspase-1, and proteinase 3 and spontaneous activation as demonstrated by the loss of CD62L. Neutrophilic activation seems to be independent from IL-1 activation and displays a gene-dose effect that may be responsible for genotype-dependent phenotypes.

Dataset Information

Mediterranean Fever gene analysis in the azeri turk population with familial mediterranean Fever: evidence for new mutations associated with disease.

Publications

Mediterranean Fever gene analysis in the azeri turk population with familial mediterranean Fever: evidence for new mutations associated with disease.

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