Clinical researchComparative screening of FMF mutations in various communities of the Israeli society
Introduction
Familial Mediterranean Fever (FMF) is an autosomal recessive disease that is widely spread in the Mediterranean region, affecting mainly Arabs, Armenians, Turks, Italians and Jews [1]. This disease is characterized by inflammation attacks accompanied by fever, which mainly occur in the synaptic tissues of the body, usually in joints, in the pleura, and in the peritoneum. The most important complication of FMF is amyloidosis, which mainly affects the kidneys, causing protein urea and leading to renal failure [2], [3], [4]. In the past, FMF has caused increased mortality as well as an evident morbidity rate, due to fatal kidney complications. However, the situation changed 35 years ago, with the advent of the use of colchicine as a type of therapy for the disease [3]. In the past, the diagnosis of FMF was solely based on clinical features, but recently molecular genetic testing has provided a definitive diagnosis.
In 1997 the gene responsible for the disease was cloned and given the name MEFV. The gene responsible for FMF — MEFV — is on the short arm of chromosome 16, and was independently identified by two positional cloning consortia [5], [6]. With the cloning of the gene, four missense mutations in exon 10 — namely M694V, V726A, M694I, and M680I — were identified [7]. These four mutations and E148Q in exon 2 are the most common MEFV mutations of the 90 putative mutations identified to date [8]. The same mutations were also commonly found in the Arab populations [9]. Exon 10 remains the major site of mutations, with a smaller cluster in exon 2. The FMF carrier rate in selected Arab populations was found to range from 11.4% to 23% [10].
The FMF gene encodes for a protein called pyrin, which is found in white blood cells; neutrophils, eosinohiles, monocytes and dendritic cells [11]. Furthermore, MEFV gene is expressed in peritoneal and skin fibroblasts but at a lower level than in neutrophils [12]. Pyrin plays an important role in regulation of inflammation, but its precise role on inflammatory pathways is still controversial. One view suggests that pyrin interacts with caspase-1 and inhibits its function. Consequently, the processing of cytokine IL-1β to its active proinflammatory form is inhibited. Thus, any defect in the pyrin structure inactivates the mechanism responsible for the prevention of the inflammatory progression [11], [13]. The function of pyrin is executed while serving as a critical component of the inflammasome complex that also includes an HIN-200 domain-containing protein together with the sensor protein of the NLR superfamily [14], [15], [16].
Israeli society is characterized by the presence of various ethnic groups namely: Jews, Arabs and Druze [17]. Several studies in relation to FMF, in various communities in general and in Israeli communities in particular, were conducted in the past [1], [2], [8], [10]. We believe that our present study is unique in terms of being comparative, involving large number of cases (1700 suspected cases) and spanning a long period of time (12 years). Thus, the purpose of our study is a comparative analysis of the various common mutations of the MEFV gene in patients from different ethnic communities of Israeli society.
Section snippets
Subjects and methods
The study group included 1700 examined patients suspected of having FMF in the “Carmel” Hospital between 1999 and 2010. Every patient directed to the outpatient clinic with clinical manifestations that aroused suspicion of FMF was referred to genetic testing. These manifestations include recurrent attacks of fever, abdominal pain, joint pain, chest pain or pleuritic pain, skin manifestation (e.g. lesions) consisting of painful erythematous areas of swelling and involvement of serosal membranes
Results
Among the 1700 suspected patients referred to the hospital, 766 (about 45%) tested negative for the suspected MEFV gene mutations investigated, while 934 (about 55%) were found to be positive. Out of the positively testing patients, 465 (49.8%) were Jews, out of which 363 (78.1%) were non-Ashkenazi Jews and 102 (21.9%) were Ashkenazi Jews. However, 274 (29.3%) were positively testing Arab patients, 237 (86.5%) of whom were Muslims and 37 (13.5%) were Christians; the remaining 195 patients
Discussion
It is well known that Familial Mediterranean Fever (FMF) is one of the most common autosomal recessive genetic disorders found in the populations of various ethnic groups in the Mediterranean basin, particularly in Turks, Armenians, non-Ashkenazi Jews and Arabs [20]. In the various ethnic communities of our study sample, the spectrum of MEFV mutations showed high heterozygosity and low homozygosity at the allelic level. It was expected that the high rates of consanguineous marriages among Arabs
Acknowledgments
We are very grateful to all patients who took part in this study. This work was partially supported by the DFG trilateral project (Reference number SCHO 754/5-1) and by the Israeli Ministry of Health. We wish to express our gratitude to them. We are also thankful to the scientific director of the Triangle Regional Research and Development Center, Dr. Ibrahim Yehya, for his cooperation and for extending to us the various facilities of the center.
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Cited by (15)
Co-occurrence of familial Mediterranean fever with systemic lupus erythematosus in South Asian population
2023, Reumatologia ClinicaCitation Excerpt :FMF is an ethnicity-specific disease of the Mediterranean region but our study demonstrated an increased propensity of co-existence of both SLE and FMF in patients of South-Asian origin as well. This is important because FMF is a prevalent disease in Jews and the above-mentioned study by Klein et al. could have inadvertently produced a selection bias with more FMF cases in the general population.15,18 However, the presence of FMF in our patient cohort demonstrates a genetic predisposition of the MEFV mutation with SLE.
MEFV gene allele frequency and genotype distribution in 3230 patients’ analyses by next generation sequencing methods
2022, GeneCitation Excerpt :While the prevalence of this disease is 1/1000 in Turks, it is 1/500 in Armenians and 1/73,000 in Ashkenazi Jews. In addition to these ethnic groups, it is also seen in Greek, Italian, and Japanese populations (Ait-Idir et al., 2017; Alparslan et al., 2020; Belmahi et al., 2012; Ebadi et al., 2017; El Roz et al., 2020; Giaglis et al., 2007; Jarjour and Jamra, 2017; Kriegshäuser et al., 2018; La Regina et al., 2003; Mansour et al., 2019; Sgouropoulou et al., 2022; Sharkia et al., 2013; Tomiyama et al., 2008). The MEFV (Mediterranean Fever) gene was first described in 1997 as a result of studies by two different groups (International FMF Consortium, 1997; French FMF Consortium, 1997).
Effects of mating patterns on genealogical trees: Assessment of the high carrier rate of Familial Mediterranean Fever in rural Israeli districts
2018, Journal of Theoretical BiologyCitation Excerpt :The M680I according to various Syrian, Lebanese Jordanian and Saudi researchers is the third-fifth most frequent FMF mutation (Sabbagh et al., 2008), fifth most frequent in Lebanon (Medlej-Hashim et al., 2005), third and fifth most frequent in Jordan (Majeed et al., 2005; Medlej-Hashim et al., 2005), and third most common FMF mutation in Syria (Rawdan et al., 2013) with a carrier rate of 1.57%.5 As to Muslim Arabs in Israel, M680I is the fifth most frequent FMF mutation (Ayesh et al., 2005; Sharkia et al., 2013) with relative allele rates of 4.4% and 12.8%, respectively. An outlying observation is that of Gershoni-Baruch et al. (2002) with the mutation M680I positioned first among Israeli Muslim Arabs FMF patients (relative rate 32.1%).
An Update on Familial Mediterranean Fever
2023, International Journal of Molecular SciencesGenetic and Epigenetic Regulation of MEFV Gene and Their Impact on Clinical Outcome in Auto-Inflammatory Familial Mediterranean Fever Patients
2023, Current Issues in Molecular Biology
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Equally contributed.