E148Q/M694I mutation in 3 Japanese patients with familial Mediterranean fever

We describe 3 unrelated Japanese patients with familial Mediterranean fever (FMF) due to a compound heterozygous E148Q/M694I mutation in the MEFV gene. The first patient is a 38-year-old man who also has chronic myelogenous leukemia (CML). Because genomic DNA analysis of the patient's nail revealed the E148Q/M694I mutation, we concluded that the individual mutations were obtained congenitally. Interferon alpha therapy was effective against not only the CML but also the FMF. The second patient is a 42-year-old man with consanguineous parents and a 14-year history of recurrent lower abdominal and back pain associated with fever. He successfully responded to colchicine treatment. The third patient is a 23-year-old woman who has a family history of FMF and since the age of 11 years has had recurrent chest and abdominal pain with fever. The onset of FMF was at an early age in this case, in contrast with the late onset of the disease in the first 2 cases. This patient's mother also has a heterozygous M694I mutation and experienced the same symptoms until 30 years of age. Our data suggest that it should be recognized that there are more FMF patients in Japan than previously expected and that the frequency of the E148Q/M694I mutation may be significant in Japanese FMF patients.     

Intrafamilial segregation analysis of the p.E148Q MEFV allele in familial Mediterranean fever

BACKGROUND: Familial Mediterranean fever (FMF) is the most frequent of the recurrent inherited fevers. This autosomal recessive disorder is characterised by periodic episodes of fever and serositis that commonly affect the people of Arab, Armenian, Sephardic Jewish and Turkish origin. Most of the described MEFV gene anomalies responsible for the disease are missense mutations. In the absence of any functional test, epidemiological studies or pedigree analyses are the only means of proving the deleterious character of these sequence variations. Evidence was provided by our recent study using a population-based approach, that the p.E148Q allele is probably a benign polymorphism and not a disease-causing mutation. Its implication in FMF remains, however, controversial. OBJECTIVE: To evaluate the segregation of the p.E148Q MEFV allele with FMF disease by using pedigree analysis. PARTICIPANTS: 21 patients and 48 unaffected relatives belonging to 18 independent families with FMF. RESULTS: Segregation analysis of the p.E148Q allele was compatible with a Mendelian autosomal recessive transmission of the disease phenotype in only three families. In 15 of 18 families, segregation was partly or completely defective. The p.E148Q allele was not transmitted to 14 of 19 (74%) affected children. CONCLUSIONS: No evidence of preferential transmission of p.E148Q from heterozygous parents to their affected offspring was observed. MEFV is not associated with the clinical manifestations of several patients carrying this variant. Considering p.E148Q to be a benign polymorphism should reduce the possibility of false-positive diagnoses, while highlighting genetic heterogeneity in FMF.     

Common MEFV mutation analysis in Iranian Azeri Turkish patients with familial Mediterranean fever

OBJECTIVES: To identify the frequency and distribution of familial Mediterranean fever (FMF) gene (MEFV) mutations among Azeri Turkish patients from northwestern Iran. METHODS: One hundred ninety unrelated patients were referred by specialists to the Molecular-Medical Genetic Center of Tabriz. A clinical diagnosis of FMF was made according to published criteria. Mutation screening of the MEFV gene was performed for the 5 most commonly known mutations, namely M694V, V726A, M680I, M694I, and E148Q, by using amplification refractory mutation system for the first 4 and by polymerase chain reaction restriction-digestion testing for E148Q. These methods may also be used as a screening tool within affected families. RESULTS: Of the unrelated patients investigated, 120 (63%) had 1 or 2 mutations. Of those with mutations, 41 were homozygous, 37 were compound heterozygous, and 42 had only 1 identifiable mutation. Of the studied alleles, the most frequent mutation was M694V (28%), followed by V726A (9%), E148Q (7%), M680I (7%), and M694I (1%) mutations. CONCLUSIONS: Our results indicate that the common Mediterranean mutations are frequent in the Azeri Turkish FMF patients but with some differences in the frequency of individual mutations. The high frequency of E148Q in Azeri Turks compared with Mediterranean ethnic groups is rather interesting. The results open the way for further investigations on patients diagnosed as having FMF and in whom no mutations or only 1 mutated allele were found.     

MEFV mutation analysis of familial Mediterranean fever in Japan

BACKGROUND: Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent attacks of fever with serosal inflammation. FMF gene (MEFV) mutations have been identified primarily in patients from Mediterranean populations. Although several clinical cases have been reported in Japan, there have been few reports to date on mutation analysis. We studied FMF patients and their relatives to examine the clinical and genetic features of this disease in the Japanese population. METHODS: Twelve Japanese FMF patients who met the Tel Hashomer criteria and a total of 17 relatives from 5 of 10 families underwent molecular genetic studies to detect MEFV mutations. The characteristics of these Japanese FMF patients and geno-phenotypical correlations were examined. RESULTS: Almost all of our patients had been suffering for a long time from fever of unknown origin and one patient also had systemic amyloidosis. In our 12 FMF patients, we detected the substitutions E84K, L110P, E148Q, R761H and M694I. We also newly diagnosed 2 relatives as having FMF based on clinical symptoms and the existence of FMF mutations. One patient was homozygous for E148Q, the patient with systemic amyloidosis was a homozygote for M694I and 4 patients from 3 families were compound heterozygotes for E148Q and M694I. Three patients in one family were compound heterozygotes for E148Q, L110P and M694I. There were 3 patients who were heterozygous for E84K, L110P-E148Q or M694I and had no other nucleotide changes in the exons of MEFV. On the other hand, 2 relatives who had never experienced symptoms of FMF were homozygous for L110P-E148Q as well as compound heterozygous for E148Q/E148Q-R761H. E148Q and M694I were the most frequently detected substitutions in our study. CONCLUSIONS: MEFV mutations occur in Japanese FMF patients though FMF is rare in Japan. The identification of MEFV mutations could be a reliable diagnostic test for FMF. The results of genetic analyses on 14 Japanese FMF patients in this study revealed that E148Q and M694I are frequent alleles.     

MEFV mutation analysis in patients suffering from amyloidosis of familial Mediterranean fever.

Familial Mediterranean fever (FMF) is a major cause of AA amyloidosis. Recently, the gene (MEFV) causing this disease was cloned and 16 disease associated mutations have been described. We have analyzed 178 FMF patients, 30 of whom also suffered from amyloidosis, for 4 mutations in MEFV. Mutations were identified in 29 of the FMF amyloidosis patients. 27 FMF amyloidosis patients were homozygous for M694V. One patient was found to be homozygous for both V726A and E148Q. In another patient E148Q and V726A were found on one allele, while V726A was found on the second allele. Amyloidosis was far more common among patients homozygous for M694V compared to patients with other mutations (P < 0.0001). In 3 patients homozygous for M694V, amyloidosis was the sole manifestation of the disease.     

Common MEFV mutation analysis in 36 Iranian patients with familial Mediterranean fever: clinical and demographic significance

The aim of our study was to determine the spectrum of the 12 most common familial Mediterranean fever gene (MEFV) mutations in Iranian patients with heterogeneous ethnicity, using the familial Mediterranean fever (FMF) strip assay test. A total of 36 patients were diagnosed according to established clinical criteria. Genomic DNA from all patients was tested for 12 common mutations located in exon 2 (E148Q), 3 (P369S), 5 (F479L), 10 [M680I (G>C), M680I (G>A), I692del, M694V, M694I, K695R, V726A, A744S, R761H], respectively, using the FMF strip assay test. Of the 35 patients with mutations, ten were homozygote, 20 were compound heterozygote, and five were heterozygote. The most frequent genotype was M680I/M680I (6 patients, 16.7%). The most frequent mutation was M680I, followed by M694V, and V726A. The FMF strip assay test for common these 12 mutations was positive in 90.6% of alleles in this study, indicating that it appears to be an effective method for FMF mutation screening in Iranian patients.     

Common MEFV mutation analysis in 36 Iranian patients with familial Mediterranean fever: clinical and demographic significance

Abstract

The aim of our study was to determine the spectrum of the 12 most common familial Mediterranean fever gene (MEFV) mutations in Iranian patients with heterogeneous ethnicity, using the familial Mediterranean fever (FMF) strip assay test. A total of 36 patients were diagnosed according to established clinical criteria. Genomic DNA from all patients was tested for 12 common mutations located in exon 2 (E148Q), 3 (P369S), 5 (F479L), 10 [M680I (G>C), M680I (G>A), I692del, M694V, M694I, K695R, V726A, A744S, R761H], respectively, using the FMF strip assay test. Of the 35 patients with mutations, ten were homozygote, 20 were compound heterozygote, and five were heterozygote. The most frequent genotype was M680I/M680I (6 patients, 16.7%). The most frequent mutation was M680I, followed by M694V, and V726A. The FMF strip assay test for common these 12 mutations was positive in 90.6% of alleles in this study, indicating that it appears to be an effective method for FMF mutation screening in Iranian patients.     

A Japanese case of familial Mediterranean fever with family history demonstrating a mutation in MEFV

We describe a 17-year-old woman with a family history of FMF who suffered from recurrent fever accompanied by pains in the left chest and abdomen. During a five-year period she experienced attacks about once every six months. The metaraminol provocative test was positive. Genomic DNA extracted from peripheral blood lymphocytes from both her and her parents were analyzed by polymerase chain reaction (PCR), followed by cycle sequencing. We detected a mutation (ATG to ATA) in codon 694 in exon 10 of the FMF gene, MEFV, that resulted in a substitution of isoleucine for methionine (M6941) in both her and her father. This is the first Japanese case of FMF with a mutation in MEFV identified in the family history.     

MEFV mutations in Tunisian patients suffering from familial Mediterranean fever

OBJECTIVES: To identify the frequency and distribution of familial Mediterranean fever (FMF) gene (MEFV) mutations in Tunisian patients. PATIENTS AND METHODS: This study was performed in the Genetic Department of Tunis University Hospital. A clinical diagnosis of FMF was made according to published criteria. Mutation screening of the MEFV gene was performed in the Human Genetic Laboratory of the "Faculté de Medecine de Tunis" for 8 mutations including the 5 most common known mutations M694V, V726A, M694l, M680l, and E148Q. The tests performed were polymerase chain reaction (PCR) restriction-digestion for M694V, V726A, M680l, R761H, E148Q; amplification refractory mutation system for A744S, M694l; and PCR-electrophoresis assay for l692del. RESULTS: Of the 139 unrelated patients investigated, 61 (44%) had 1 or 2 mutations. In 78 (56%) probands no mutation was identified: 28 patients were homozygous; 16 were compound-heterozygous; 2 had complex alleles; and 17 had only 1 identifiable mutation. Of the mutations, M680l, M694V, M694l, V726A, A744S, R761H, l692DEL, and E148Q accounted for 32, 27, 13, 5, 3, 1, 1, and 18%, respectively. CONCLUSION: The profile of the MEFV gene mutations in the Tunisian population is concordant with other Arab populations but with some differences. M680l is the most common mutation, while V726A, the commonest mutation among Arabs, is rare in our population.     

Periodic fever due to a novel TNFRSF1A mutation in a heterozygous Chinese carrier of MEFV E148Q

SIR, The hereditary periodic fever syndromes are characterizedby recurrent episodes of fever due to multisystemic inflammation.In the case of autosomal dominantly inherited tumour necrosisfactor (TNF) receptor-associated periodic syndrome (TRAPS),these attacks are associated with severe abdominal pain, localizedmyalgia, painful migratory erythematous skin rash, conjunctivitisand/or periorbital oedema. TRAPS is caused by sequence alterationsin the TNFRSF1A gene, which encodes the 55-kDa TNF receptor[1]. Familial Mediterranean fever (FMF) is the most common autosomalrecessively inherited periodic fever syndrome. Attacks of FMFare of 1–3 days’     

A Japanese patient with familial Mediterranean fever associated with compound heterozygosity for pyrin variant E148Q/M694I

Familial Mediterranean fever (FMF) is an inherited inflammatory disease occurring mainly in Mediterranean and Middle Eastern populations. FMF is caused by mutations in the MEFV gene that encodes pyrin/marenostrin. Here, we report a Japanese female FMF patient with heterozygosity for the compound pyrin E148Q/M694I showing recurrent fever, serositis or delay in skin wound healing. Her father and elder sister were heterozygous for pyrin variant M694I alone and sometimes suffered from mild fever or delay in wound healing, but her mother was heterozygous for pyrin variant E148Q alone and had no symptoms. This suggested that the inheritance of FMF occurred not only in an autosomal recessive manner but also in an autosomal dominant manner in this Japanese family, and the severity of the disease differed among the family members in relation to the mutation. In the treatment of FMF, colchicine, reserpine or prazosin hydrochloride have been reported to prevent the attacks, but, in our patient such drugs were ineffective or caused side effects, and only the anti-allergic drug azelastine was of benefit in relieving the attacks.     

Frequency of familial Mediterranean fever (MEFV) gene mutations in patients with biopsy-proven primary glomerulonephritis

Clinical Rheumatology - Primary glomerulopathies are those disorders that affect glomerular structure, function, or both in the absence of a multisystem disorder. We aimed to evaluate the frequency...