Elsevier

Gene

Volume 568, Issue 2, 1 September 2015, Pages 170-175
Gene

Research paper
Familial Mediterranean fever gene mutations in north-eastern part of Anatolia with special respect to rare mutations

https://doi.org/10.1016/j.gene.2015.05.045Get rights and content

Highlights

  • We determine the prevalence of rare mutations of the MEFV gene in Northeastern Anatolia.

  • The rare mutations were M694I, E148V, T267I, L110P, E167D, K695R and a new mutation.

  • Rare mutations for FMF may not be as rare as they were previously thought to be.

Abstract

We aimed to determine the frequency of mutations, carrier rates and the association of rare mutations with Familial Mediterranean Fever (FMF) symptoms. There is a need to evaluate as many different populations as possible in order to determine either specific rare mutations or a range of disease-associated mutations. The demographic data and FMF symptoms related to MEFV gene mutations were collected from 731 participants. Exon 2 and exon 10 of the MEFV gene were tested by DNA sequencing. The rare mutations were identified as: M694I (1.1%, n = 12), E148V (0.6%, n = 6), T267I (0.5%, n = 5), L110P (0.2%, n = 2), E167D (0.2%, n = 2), K695R (0.1%, n = 1) and an insertion G (Guanine) mutation (0.4%, n = 4) at the 777th codon of exon 10. We used routine comprehensive detection systems such as Sanger sequence that can catch rare mutations, for definite diagnosis and treatment of FMF disease.

Introduction

Familial Mediterranean fever (FMF) is a hereditary auto-inflammatory disorder characterised by recurrent attacks of fever and abdominal pain with serositis, arthritis and skin lesions. Renal failure due to amyloidosis is the most important complication of this disease (Ozdemir et al., 2011, Tunca et al., 2005). The disease shows an autosomal recessive pattern of inheritance. The gene associated with Mediterranean fever (MEFV), which predominantly affects people of Mediterranean descent (especially Turks, Armenians, Jews and Arabs), is responsible for FMF (Medlej-Hashim et al., 2011, Tunca et al., 2005).

The MEFV gene, comprises of 10 exons, is located on the short arm of chromosome 16 at the position p13.3 and encodes for the 781 amino-acid protein named as pyrin or marenostrin (OMIM Protein Accession Number: NP_000234.1) (Consortium TFF, 1997, Consortium TIF, 1997; http://www.ncbi.nlm.nih.gov/). Although the pyrin function is not yet fully understood, it plays role in the modulation of apoptosis, inflammation, and cytokine processing, and is thought to down-regulate the inflammation process in polymorph nuclear cells. Pyrin also is attached to the adaptor apoptosis-associated speck-like protein (ASC) and takes a role in stimulating pro-caspase-1 that leads to the regulation of IL-1b, and IL-18 expression (Guz et al., 2009). Accordingly, an abnormality in this protein will induce an inappropriate inflammatory reaction, as occurs in the attacks of FMF. Detection of illness-causing mutations plays a crucial role in supporting the diagnosis, because it is difficult to establish a clinical diagnosis for FMF (Aldea et al., 2004, Ozdemir et al., 2011).

To date, the Infevers database reports 305 gene mutations and polymorphisms in the MEFV gene (Infevers, 2015). The most frequent mutations are described in exon 2 and exon 10, but the spectrum of MEFV mutations in FMF patients differs among ethnic groups and populations (Dundar et al., 2011). Most of the mutations are common mutations, and there are some other rare mutations with low frequencies. The MEFV gene is very polymorphic and might also exist across populations of different ethnicities. Moreover, a common mutation that is reported frequently in an ethnic group might not be frequently found in the other ethnicities (Guz et al., 2009). So far, rare mutation frequencies in the Turkish population and its association with FMF have not been studied sufficiently.

In this study, we report 1620 subjects with the suspicion of FMF in the north-eastern part of Anatolia. We analysed exon 2 and exon 10 of the MEFV gene using DNA sequencing. We aimed to determine the frequency of the rare mutations, the carrier rates and the association of these mutations with FMF symptoms.

Section snippets

Materials and methods

We investigated 1620 subjects with the suspicion of FMF that referred to the Department of Medical Biology unit for MEFV mutation analyses between 2011 and 2013 (Fig. 1). A total of 731 subjects with mutations were included in the study. Twenty-seven of the subjects with rare mutations were symptomatic patients that exhibited at least one FMF symptom: Recurrent abdominal pain and recurrent attacks of fever followed by arthritis, chest pain with pleuritis and renal symptoms. To better identify

Results

The cohort was composed of 1620 subjects: 911 (56.2%) were females and 709 (43.8%) were males. The subjects' age distribution ranged between 1 and 72 years and the median age was 16. The mean age of mutation carrier genotypes was significantly higher than the mean age of the wild types (20.5 ± 15.1 vs. 17.3 ± 12.1; p < 0.0001). Mutations were identified in 731 (45.1%) subjects and no mutation was found in 889 (54.9%) subjects (Fig. 1). The MEFV mutation was found in 46.5% (n = 424) of the 911 females

Discussion

In this study, we report the distribution of MEFV gene mutations among the suspects of MEFV gene mutations carriers in north-eastern Turkey. The current results of 1620 subjects revealed that 46.4% (731) of them were carriers of the MEFV mutation. The most common mutation frequency was M694V (43.2%), followed by V726A (16.1%), E148Q (14.6%), M680I (G/C) (14.4%), R761H (6.7%) and A744S (2.3%), and the frequency of all rare mutations was 3.0%. On the other hand, Yilmaz et al. (2001) detected that

Acknowledgement

None declared.

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