MEFV alterations and population genetics analysis in a large cohort of Greek patients with familial Mediterranean fever

Familial Mediterranean fever (FMF) is a disease characterized by recurrent, self-limiting bouts of fever and serositis and caused by altered pyrin due to mutated MEFV gene. FMF is common in the Mediterranean Basin populations, although with varying genetic patterns. The spectrum and clinical significance of MEFV alterations in Greece has yet not been elucidated. The aim of this study was to analyze the spectrum of MEFV alterations in FMF patients and healthy individuals in Greece. A cohort of 152 Greek FMF patients along with 140 Greek healthy controls was enrolled. Non-isotopic RNase cleavage assay (NIRCA) and sequencing allowed mutational and haplotypic analysis of the entire coding sequence of MEFV. The ARLEQUIN 2.0, DNASP 4.0 and PHYLIP software were used for population genetics analysis. Among patients, 127 (83.6%) carried at least one known mutation. The most common mutations identified were M694V (38.1%), M680I (19.7%), V726A (12.2%), E148Q (10.9%) and E230K (6.1%). The total carrier rate among healthy individuals was 0.7%. The presence of R202Q homozygosity in 12 of the remaining 25 MEFV negative FMF patients might be considered as disease related in Greeks. Population genetics analysis revealed that Greeks rely closer to the eastern rather than western populations of the Mediterranean Basin.     

Mutations in the MEFV gene in a large series of patients with a clinical diagnosis of familial Mediterranean fever

Familial Mediterranean fever (FMF) is an autosomal recessively inherited disease affecting patients of the Mediterranean basin. FMF is characterized by recurrent episodes of fever accompanied with topical signs of inflammation. Some patients can develop a renal amyloidosis associated (AA) amyloidosis. The administration of colchicine is an effective preventive treatment of both the attacks and amyloidosis. The FMF gene (MEFV) was cloned and missense mutations were found to be responsible for the disease. We investigated a large series of 303 unselected and unrelated patients of various ethnic backgrounds with a clinical suspicion of FMF to confirm or invalidate the diagnosis of FMF and to determine the spectrum of MEFV mutations. Molecular analysis focused on all the most frequent mutations identified so far, and an exhaustive analysis of exon 10, containing the mutational hotspot, was performed through DNA sequencing. Sixty-two percent of Sephardic, North African Arabs, Armenian and Turkish patients were either homozygous or compound heterozygous for MEFV mutations. In other populations surrounding the Mediterranean Sea such as Greek, Italian, Portuguese, Kurdish and Lebanese populations, mutations were also found. In general, patients without Mediterranean origin had no mutations in the MEFV gene. Two new mis-sense mutations were identified in exon 10 of the MEFV gene: the S675N in an Italian patient and the M680L in a French patient without any known at-risk ethnic ancestry.     

Familial Mediterranean fever: MEFV gene mutations and treatment]

Familial Mediterranean fever (FMF) is an autosomal recessive disease which predominantly affects certain ethnic groups mainly Sephardic Jews, Turks, Arabs and Armenians. FMF has been rarely reported in Japan. Characteristic symptoms include self-limited recurrent attacks of fever with serositis such as peritonitis, pleuritis, and arthritis. The most serious complications of FMF are secondary AA amyloidosis and subsequent chronic renal failure. FMF is caused by mutations in MEFV gene which encodes a protein called pyrin. Pyrin regulates processing of IL-1beta, NF-kappaB activation and apoptosis. Dysregulated function of pyrin results in excessive production of proinflammatory cytokine thereby evoking inflammatory attacks. The mainstay of treatment is colchicine which is effective for both relieving symptoms and preventing secondary amyloidosis.     

Common MEFV mutations among Jewish ethnic groups in Israel: high frequency of carrier and phenotype III states and absence of a perceptible biological advantage for the carrier state

Familial Mediterranean fever (FMF) is an autosomal recessive disease, characterized by recurrent attacks of fever and inflammation of serosal membranes and gradual development of nephropathic amyloidosis. The recent cloning of the FMF gene (MEFV) and identification of disease-associated mutations in most patients made the direct determination of FMF carrier frequency feasible. The aim of the present study was to investigate the carrier rate of the most common MEFV mutations among different Jewish ethnic groups in Israel. Further, an attempt was made to elucidate the possible biological advantage that the heterozygote state may confer. Three hundred Ashkenazi, 101 Iraqi, and 120 Moroccan Jews were screened for the E148Q, V726A, and M694V mutations (at least two most common mutations per group), with a resulting overall carrier frequency in the respective ethnic group of 14%, 29%, and 21%. No difference in morbidity between Ashkenazi carriers and non-carriers of MEFV mutations was discerned, although an excess of febrile episodes in carriers of the V726A and in carriers of either V726A or E148Q was evident (P < 0.02 and P < 0.05, respectively). The frequency of subjects with two MEFV mutations but not expressing FMF (phenotype III) was 1:300 in Ashkenazi Jews and 1:25 in Iraqi Jews, exceeding the reported rate of overt FMF in these ethnic groups by 40-240 fold. These results affirm the high carrier rate among the studied Jewish ethnic groups in Israel and suggest that most subjects with FMF mutations are unaffected.     

Familial Mediterranean fever in the 'Chuetas' of Mallorca: a question of Jewish origin or genetic heterogeneity

Familial Mediterranean fever (FMF) is a hereditary disease commonly found among Jews, Armenians, Turks and Arabs. Recently, FMF was found in the 'Chuetas', a unique community on the island of Mallorca (Spain). To address the question of their possible Jewish origin, we analysed markers known to be linked to the gene responsible for FMF in Jews (MEFV) in this population. We found that 1/3 of the 16p13.3 chromosomes of the 'Chuetas' FMF patients bore the major ancestral haplotypes (S,S2) and their corresponding M694V and E148Q mutations, displayed by Jews from North Africa. Furthermore, we also detected a novel mutation (L110P) in this community. Yet 2/3 of these patients bore S negative haplotypes and lack the mutations commonly known to cause FMF. These results confirm that at least some of the 'Chuetas' share a common origin with Jews. However, they also provide evidence for the possibility of genetic heterogeneity in this disorder.     

Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF)

Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurring attacks of fever and serositis. It affects primarily North African Jews, Armenians, Turks and Arabs, in which a founder effect has been demonstrated. The marenostrin-pyrin-encoding gene has been proposed as a candidate gene for the disease ( MEFV ), on the basis of the identification of putative mutations clustered in exon 10 (M680V, M694I, M694V and V726A), each segregating with one ancestral haplotype. In a search for additional MEFV mutations in 120 apparently non-founder FMF chromosomes, we observed eight novel mutations in exon 2 (E148Q, E167D and T267I), exon 5 (F479L) and exon 10 (I692del K695R, A744S and R761H). Except for E148Q and K695R, all mutations were found in a single chromosome. Mutation E148Q was found in all ethnic groups studied and in association with a novel ancestral haplotype in non- Ashkenazi Jews (S2). Altogether, these new findings definitively establish the marenostrin/pyrin-encoding gene as the MEFV locus.      

Familial Mediterranean fever in a large Lebanese family: multiple MEFV mutations and evidence for a Founder effect of the p.[M694I] mutation

Familial Mediterranean fever (FMF) is an autoinflammatory autosomal recessive disease characterized by recurrent fever crises and serous inflammation. The MEFV gene responsible for the disease was identified on chromosome 16, and 5 of the mutations discovered so far in the gene are most frequently encountered in FMF patients: p.[M694V], p.[V726A], p.[M680I] and p.[M694I] in exon 10, and p.[E148Q] in exon 2. The present work describes multiple MEFV mutations and the corresponding haplotypes for 31 FMF patients as well as 32 "healthy" individuals of a large consanguineous Lebanese family. The DNAs were screened for MEFV mutations, and determination of the corresponding haplotypes was performed for all individuals by genotyping 4 microsatellites surrounding the gene. Five different mutations were detected in this one family, which is unexpected in such a genetic isolate. A phenotypic variability was also observed. The haplotype carrying the p.[M694I] allele, detected in all the family branches, was well conserved and therefore seems to be the ancestral one.     

The significance of paired MEFV mutations in individuals without symptoms of familial Mediterranean fever

The majority of patients with familial Mediterranean fever (FMF) have identifiable mutations in both alleles of the MEFV gene, while some individuals with paired MEFV mutations do not have clinical symptoms of the disease. During family studies we identified nine such individuals from six kindreds, most of whom either subsequently developed FMF or had other clinically significant inflammatory disease; one case benefiting substantially from colchicine therapy. Four individuals remained asymptomatic. Two further asymptomatic subjects with paired MEFV mutations were identified among 49 healthy controls from western Turkey, of whom a further 18.4 per cent were simple heterozygotes. This carrier rate was higher than would be expected from prevalence of FMF in this region, suggesting that penetrance of paired recognised pathogenic MEFV mutations may frequently be incomplete. MEFV genotyping results must be interpreted with due caution, and follow-up of apparently asymptomatic subjects with paired mutations is advisable.     

Familial Mediterranean Fever in Crete: a genetic and structural biological approach in a population of 'intermediate risk'

Familial Mediterranean Fever (FMF) is an autosomal, recessively inherited disease, characterized by recurrent and short attacks of fever with serosal inflammation that are caused by mutations in MEFV gene that encodes pyrin protein. To date, more than 70 disease-associated mutations have been identified, almost all of them representing missense nucleotide changes. FMF is very common among patients with Mediterranean ancestry, although the exact prevalence is not yet known, Greeks are considered to be at 'intermediate risk'. In the present study, we studied FMF patients in natives of Crete, a population sharing a common genetic and cultural background. The spectrum of MEFV gene mutations in 71 patients as well as 158 healthy controls was studied by performing a molecular analysis focused on the 12 most frequent FMF-associated mutations. We found that 59 of 71 (83.1%) FMF patients had at least one MEFV mutation, five patients were homozygotes and 54 heterozygotes for FMF-associated mutations. No mutations were detected in 12 patients (16.9%). As in high-risk populations, common MEFV mutations were found in Cretan FMF patients, with the M694V being the most penetrant. M694V and M694I mutations were associated with severe phenotypes, with many patients presenting with uncommon clinical manifestations such as erysipelas-like erythema or renal disturbances. Of interest, 20 (37%) of our heterozygous FMF patients presented with a severe phenotype. Population genetics analysis showed an FMF carrier frequency in healthy Cretan population of approximately 6% (1:17) and places Cretans closer to the Western rather than Eastern populations of the Mediterranean basin. Finally, we constructed a three-dimensional model showing the interaction of the PRYSPRY domain of pyrin with caspase-1 onto which we mapped MEFV mutations, classified according to disease severity. In this model, the 'flexible loops' of caspase-1 appear to have no access to some positions that have been previously associated with mild disease, suggesting that alternative pathogenic pathways leading to FMF need to be explored.     

MEFV mutation frequencies in a Turkish cohort with low prevalence of familial Mediterranean fever

Background/aimFamilial Mediterranean fever (FMF) is a genetically recessive autoinflammatory disease caused by mutations in the Mediterranean fever (MEFV) gene. The aim of this study was to investigate the frequencies of the most common MEFV mutations among a sample of healthy individuals from the Havsa population of European Turkey, where FMF is less prevalent compared to Asian Turkey.Materials and methodsThe study group consisted of 263 unrelated healthy adults. All of the participants were analyzed for the M694V, V726A, M680I, and E148Q mutations in the MEFV gene.ResultsIn total, 25 of the 263 individuals carried MEFV mutations (9.5%). The observed allele frequencies were 1.5% for M694V (95% confidence interval [CI] 0.5-2.5), 2.6% for E148Q (95% CI 1.6-3.9), 0.5% for M680I (95% CI 0.0-1.1), and 0.0% for V726A. The frequencies of the M694V, M680I, and E148Q mutations were not significantly different from allele frequencies (approximately 20%) determined for other regions of Turkey where FMF is more prevalent.ConclusionThese data suggest that the positivity of the MEFV gene mutation tests have lower predictive value in a population with low FMF prevalence.     

MEFV mutations in Turkish patients suffering from Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is a recessive inherited disorder affecting Sephardic Jews, Arabs, Armenians and Turks. The gene responsible for FMF was recently cloned and several disease-associated mutations have been described. We have evaluated seven MEFV mutations in 460 chromosomes of 230 unrelated patients with FMF living in Turkey, using PCR methods. The M694V allele accounted for 43.5% of the alleles studied and 19.1% of the patients were homozygous. The M680I, V726A and M694I mutations were responsible for 12.0%, 11.1% and 2.8% of the patients respectively. R761H, K695R and E148Q were rarely encountered. Two thirds of the disease alleles were attributed to three common mutations: M694V, M680V and V726A, but only 54% of the patients carried one or two of the three mutations. Adding the four rarer mutations increased these figures to 72% and 60%, respectively. Altogether, 79.6% of the patients bore at least one of the main mutations, and 84.3% carried at least one of the seven mutations studied. The 28 patients suffering also from amyloidosis carried at least one of five mutations, M694V being the most common. These results suggest that the origin of FMF in Turkey is heterogenous, all common mutations are associated with amyloidosis. Further, rapid and accurate molecular diagnosis of FMF is feasible in most cases.     

Familial Mediterranean fever (FMF) phenotype in patients homozygous to the MEFV M694V mutation

The clinical presentation of familial Mediterranean fever (FMF) is remarkably variable, ranging from a quiescent to a severe and disabling disease. The M694V mutation is one of approximately 300 published genetic variations in the FMF gene. While some studies have reported a more severe phenotype for the homozygous M694V mutation, studies dedicated solely to featuring the phenotype of homozygous M694V genotype are meager. The objective of the study was to present a comprehensive characterization of the homozygous M694V mutation associated phenotype, compared to the phenotypes of other FMF genotypes. For that aim, we compared between the demographic and clinical characteristics of 57 FMF patients, homozygous for the M694V MEFV mutation, and 56 patients with other MEFV genotypes. A questionnaire, detailing demographic and clinical features was completed for each patient based on an interview, physical examination and medical file data. Compared with the control group, the double M694V MEFV mutation group comprised more patients with severe disease (89.4 vs. 32.1%, p < 0.0001) and affected with FMF-related comorbidities (29.8 vs. 12.5%, p = 0.0373). The mean frequency of attacks per year was higher for patients with the double M694V MEFV mutation, before and during colchicine treatment (23.6 ± 9.3 vs.15.6 ± 11.7, p = 0.0001 and 7.2 ± 7.8 vs. 3.5 ± 5.5, p = 0.0007, respectively); and the mean dose of colchicine used was higher (1.9 ± 0.48 vs.1.48 ± 0.54 mg/day, p = 0.0001).Among the genotypes tested, homozygosity to the M694V MEFV mutation was found to be associated with the most grievous phenotype in the clinical spectrum of FMF.     

Analysis of common MEFV mutations in Egyptian patients with familial Mediterranean fever: molecular characterisation of the disease

Familial Mediterranean fever (FMF) is a hereditary inflammatory disorder transmitted as an autosomal recessive trait. It predominantly affects people living in, or originating from, areas around the Mediterranean and was difficult to diagnose until mutations in the MEFV gene were identified. This study aims to analyse the five most common MEFV mutations in Egyptian patients diagnosed clinically as FME Thirty-eight unrelated patients were tested for the presence of the MEFV gene mutations V726A, M694V, M694I, M680I and E148Q, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and the amplification refractory mutation system (ARMS). Twenty-three patients (60.5%) had one or more mutations, whereas no mutation was found in the remaining 15 patients (39.5%). The most common mutation was M694I (42.5%), followed by V726A (22.5%), M680I (17.5%) and E148Q (17.5%). The M694V mutation was not detected. The profile of MEFV gene mutations in this study suggests that the origin of FMF in Egypt is heterogeneous, a finding in concordance with that for other Arab populations; however, some differences were observed as M694V, the most common mutation reported in Arabs, was not detected in this study.     

The spectrum of Familial Mediterranean Fever (FMF) mutations.

Familial Mediterranean Fever (FMF) is the prototype of a group of inherited inflammatory disorders. The gene (MEFV) responsible for this disease, comprises 10 exons and 781 codons. Twenty-nine mutations, most located in the last exon, have been identified so far. It is unclear whether all are true disease-causing mutations. Five founder mutations, V726A, M694V, M694I, M680I and E148Q account for 74% of FMF chromosomes from typical cases (Armenians, Arabs, Jews, and Turks). Rare mutations are preferentially found in populations not usually affected by FMF (eg Europeans not from the above ancestries). The various combinations of MEFV mutations define severe to mild genotypes. The trend is that genotypes including two mutations located within mutational 'hot-spots' (codons 680 or 694) of the gene are associated with severe phenotypes, whereas mild phenotypes are associated with some other mutations, E148Q being the mildest and least penetrant. Understanding the correlation between the FMF phenotype and genotype is further obscured by the existence of complex alleles, modifier loci, genetic heterogeneity and possible epigenetic factors. Additionally, mutations in the MEFV gene are thought to be involved in non FMF disorders. Carrier rates for FMF mutations may be as high as 1:3 in some populations, suggesting that the disease is underdiagnosed. This review update emphasises that both clinical and genetic features are to be taken into account for patient diagnosis, colchicine treatment and prognosis.     

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

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.     

A single mutated MEFV allele in Israeli patients suffering from familial Mediterranean fever and Behçet's disease (FMF-BD)

Although familial Mediterranean fever (FMF) is an autosomal recessive disorder, preliminary partial mutation analysis suggested that about 60% of FMF patients, who also suffer from Beh?et's disease (FMF-BD), have only a single mutated FMF gene (MEFV). In this study, the possibility that patients with FMF-BD may indeed be carriers of a single mutated MEFV is further analysed. The presence of mutations in the coding region of MEFV of eight patients with FMF-BD, representing six families with 47 members, was determined by sequencing. A possible role for the non-carrier chromosome and for BD in the expression of FMF in patients with a single mutated MEFV allele was determined by analysing the association between these variables and the presence of FMF in heterozygous kin. Sequence analysis revealed that all eight patients had indeed only one mutation in the coding region of MEFV. The patients' non-carrier chromosomes converged into three different MEFV haplotypes and were shared by heterozygous unaffected kin in five of six families. BD was found in 10 of 11 carriers with FMF vs one of 16 carriers without FMF (P < 0.001). These results suggest that FMF may be expressed in individuals harbouring only one coding mutation in MEFV. The findings argue against a role for the non-carrier chromosome in the induction of FMF, and suggest that the FMF phenotype in this cohort was associated with the simultaneous presence of BD. These findings may mirror a more generalised rule, that FMF may be precipitated in carriers of a single mutated FMF gene by factors unrelated to the other MEFV allele.     

Familial Mediterranean fever is no longer a rare disease in Italy

Familial Mediterranean fever (FMF) is an autosomal recessive disorder, characterised by short, recurrent attacks of fever with abdominal, chest or joint pain and erysipelas-like erythema. It is an ethnically restricted genetic disease, found commonly among Mediterranean populations, as well as Armenians, Turks, Arabs and Jews. Traditionally, Italians have been considered little affected by FMF, despite the geographical position of Italy (northern Mediterranean basin) and the migratory changes in its population. The objective was to characterise the demographic, clinical and genetic features of FMF in Italy. Patients of Italian origin were recruited from those referred to Italian-French medical centres for FUO (Fever of Unknown Origin) or 'surgical' emergencies; clinical history, genealogy and physical examination were recorded; all other possible infectious, neoplastic, auto-immune and metabolic diseases were excluded. Mutational analysis of the gene responsible for FMF (MEFV on 16p13.3) was performed, after which geno-phenotypical correlations were established. Italian FMF patients, 40 women and 31 men, aged from 3 to 75 years, have shown all the clinical manifestations indicative of FMF described in the literature, but with a lower incidence of amyloidosis. The genetic tests have been contributive in 42% of cases. The frequency of each different mutation has been similar to that found in a series of 'endemic' countries. The geno-phenotypical correlations have suggested the existence of genetic and/or environmental modifier-factors. Among Italians FMF seems to be more frequent than was believed in the past. The data presented are consistent with their geographical location and their history.     

Clinical differences between North African and Iraqi Jews with familial Mediterranean fever

Familial Mediterranean fever (FMF) is an autosomal recessive disease causing attacks of fever and serositis. The gene causing this disease, designated MEFV, was mapped to the short arm of chromosome 16, but has not yet been cloned. North African and Iraqi Jews constitute the two largest population groups suffering from the disease in Israel. In this report we compared the severity of the disease between these two populations. North African Jews were found to have a more severe disease manifested by an earlier age of onset, an increase in frequency and severity of joint involvement, a higher incidence of erysipelas-like erythema, and a higher dose of colchicine required to control symptoms. The involvement of additional genes, environmental factors, and different mutations in MEFV, may explain the clinical variation in disease severity between these two population groups. Am. J. Med. Genet. 75:216–219, 1998. © 1998 Wiley-Liss, Inc.