Comparative screening of FMF mutations in various communities of the Israeli society

Abstract

Familial Mediterranean Fever (FMF) is an autosomal recessive disease that is widely spread in the populations of the Mediterranean region. It is characterized by recurrent fever and inflammatory attacks. A total of 1700 suspected patients, belonging to various communities in Israel: Jews (Ashkenazi and non-Ashkenazi), Arabs (Muslims and Christians) and Druze, was subjected to examination for FMF mutation screening. The patients were screened for the most common six MEFV gene mutations namely, M680I, M694V, M694I, V726A, E148Q and K695R. Fifty-five percent of the cases were confirmed to have MEFV mutations. The most common mutations among all the cases studied were M694V, E148Q and V726A. The common mutations in the respective communities were: among the Jews M694V with a frequency of 69.9% (76.8% for non-Ashkenazi Jews and 43.6% for Ashkenazi Jews), among the Arabs V726A with a frequency of 32.7% (32.7% for Muslims and 32.1% for Christians) and among Druze it was E148Q with a frequency of 52.1%. The characteristic mutation present in Jews was K695R and the one in Arabs was M680I, while no characteristic mutation was found in Druze. On the other hand, mutation E148Q was observed to have a considerable occurrence in patients of all ethnic groups studied. Furthermore, our results revealed that homozygous mutations accounted for 168 cases (18%). The homozygote mutation M694V was the most prevalent among Jews and the E148Q mutation was the most common among Druze, while, among Arabs there were three homozygous mutations having maximum prevalence, namely, V726A, M694V and M694I. Our study comprehensively provided a spectrum of FMF mutations in various communities of 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.