Increased Frequency of Mutations in the Gene Responsible for Familial Mediterranean Fever (MEFV) in a Cohort of Patients with Chronic Idiopathic Neutropenia

Abstract Introduction-Aim: Chronic idiopathic neutropenia (CIN) is a neutrophil disorder characterized by the prolonged and unexplained reduction in the number of peripheral blood (PB) absolute neutrophil counts (ANC). The underlying pathogenesis in CIN implicates the production of proinflammatory cytokines by activated lymphocytes and monocytes that induce excessive apoptotic death of the bone marrow (BM) granulocytic progenitor cells. Clonal hematopoiesis identified by next generation sequencing (NGS) of myeloid genes is found in 11% of CIN patients conferring an increased risk for MDS/AML transformation whereas the non-clonal patients display usually a benign course. The basis for the immune cell activation and proinflammatory cytokine production in CIN remains obscure. Based on previously reported data showing increased frequency of mutations of the MEFV gene encoding pyrin in patients with idiopathic inflammatory conditions other than typical Familial Mediterranean Fever (FMF), we sought to investigate the common MEFV mutations in a cohort of well characterized CIN patients. Patients-Methods: We have studied 50 patients fulfilling the previously reported diagnostic criteria of CIN (median ANC 1.5x10 9/L, range 0.2-1.7 x10 9/L), 44 females and 6 males with a median age of 56 years (range 25-87 years) and a long-follow-up (median 132 months, range 8-336 months) in the Department of Hematology of the University Hospital of Heraklion, Crete, Greece. Nonisotopic RNase cleavage assay (NIRCA) analysis was used as first screening method to detect MEFV exons 10 and 2 mutations in DNA extracted from PB or BM samples from CIN patients, confirmed by direct NGS analysis. These sequences contain the main disease-related mutations and polymorphisms. Results: Genetics alterations of MEFV were detected in 22 out of 50 CIN patients (44%). Pathogenic mutations (variants associated with typical or "atypical" FMF phenotype in Greek population) were identified in 10/50 CIN patients (20%). The 20% frequency of MEFV mutations in exon 10 and/or exon 2 in CIN patients is significantly higher compared to the carrier rate of common MEFV mutations in the healthy Greek population (0.7%) according to our previously reported data (P<0.0001, Fisher's exact test). NGS analysis confirmed the mutational pattern of NIRCA and specifically showed: (a) one patient with heterozygous I720M (ATC>ATG; Ile>Met), two patients with heterozygous A744S (GCC>TCC; Ala>Ser) and one with homozygosity, one patient with heterozygous M694V (ATG>GTG; Met>Val), one with heterozygous K695R (AAG>AGG; Lys>Arg) and one with heterozygous M680I (ATG>ATC; Met>Ile), all in exon 10, and (b) four patients with homozygous R202Q mutation in exon 2 (one patient with homozygous A744S co-mutation in exon 10) and two patients with R202Q heterozygosity combined with heterozygosity of I720M and A744S of exons 10, respectively. None of the patients displayed any symptoms/signs of FMF or other systemic inflammatory disease. No statistically significant differences were identified between MEFV mutated and non-mutated CIN patients in the severity of neutropenia or in lymphocyte, monocyte, hemoglobin and platelet counts. A significant difference was identified between the two patient groups in serum IgG (1440±264 vs 1133±245 mg/dl; P = 0.0023, Mann-Whitney test) but not IgA or IgM levels. Discussion: This study reports for the first time that 20% of unselected, consecutive patients with CIN carry mutations of the MEFV gene without clinical manifestations of FMF. Whether these patients represent atypical cases of FMF or the identified MEFV genetic alterations have a pathogenetic/modifying effect in the inflammatory responses associated with CIN is an open/novel field of research. As a first step we are currently investigating the neutrophil autophagic status, IL-1β production and the neutrophil extracellular trap (NET) formation in CIN patients with mutations in MEFV to clarify their potential effect in the immune deregulation known to characterize CIN. Disclosures No relevant conflicts of interest to declare.

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R761H M694I, M694V, V726A, R202Q, M680I AND E148Q MEFV GENE (FAMILIAL MEDITERRANEAN FEVER GENE) MUTATIONS IN THE AZERBAIJANİAN PATİENTS

Ambiance in Life International Scientific Journal in Medicine of Southern Caucasus ◽

10.36962/0601202150 ◽

2021 ◽

Vol 06 (01) ◽

pp. 50-51

Author(s):

Huseynova Lala Huseynova Lala ◽

Huseynova Qumru Huseynova Qumru

Keyword(s):

Familial Mediterranean Fever ◽

Mediterranean Region ◽

Phenotypic Variability ◽

Mefv Gene ◽

Eastern Mediterranean Region ◽

Nucleotide Sequences ◽

Exon 2 ◽

Mediterranean Fever ◽

The Republic ◽

Exon 10

MEFV gene (Familial Mediterranean Fever Gene) is located on chromosome 16 - 16.13.3., and it is composed of 3,242,028-3,256,776 nucleotides. It is specified as having an autosome-recessive hereditary type. Autosome-dominant hereditary species were also recorded(2,4). The MEFV RoRet genes family contains exon 10, consisting of 10,000 nucleotide sequences(5). The length of the transcript consists of 3.7 thousand nucleotide sequences consisting of 761 synthesized pyridine protein amino acid bases(1,3) MEFV gene researches were performed in the population of the Republic of Azerbaijan. Over 80 mutations have been identiﬁed so far. Four missense mutations (M680I, M694V, M694I, and V726A) in exon 10, together with E148Q in exon 2, account for the majority of FMF mutations in populations originating from areas around the eastern Mediterranean region. The various combinations of MEFV mutations are largely associated with the phenotypic variability of the disease. The most serious complication of FMF is the development of renal amyloidosis, which may be the only manifestation of the disease. The molecular-genetic study of the MEFV gene isolated from the genome DNA of 18 patients suspected of Family Disease Fever has identified 7 mutations: R761H M694I, M694V, V726A, R202Q, M680I and E148Q. All patients were of Azerbaijan origin, from the Mediterranean region of Azerbaijan. They were evaluated for clinical findings and family history of FMF. Seven mutations of MEFV gene were identified in heterozygous, homozygous and compound conditions: R761H M694I, M694V, V726A, R202Q, M680I and E148Q. The mutations E148Q and R202Q were discovered in exon 2 and R761H M694I, M694V, V726A, M680I were found in exon10 in the population of the Republic of Azerbaijan.

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SAT0527 COMBINED EFFECT OF COMMON VARIANTS IN EXON 2 OR EXON 3 AND A PATHOGENIC MUTATION IN EXON 10 OF THE MEDITERRANEAN FEVER GENE ON INFLAMMASOME ACTIVATION IN JAPANESE PATIENTS WITH FAMILIAL MEDITERRANEAN FEVER

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5475 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1221.2-1221

Author(s):

T. Koga ◽

Y. Endo ◽

K. Furukawa ◽

K. Agematsu ◽

A. Yachie ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Japanese Patients ◽

Pathogenic Mutation ◽

Inflammasome Activation ◽

Combined Effects ◽

Common Variants ◽

Thoracic Pain ◽

Exon 2 ◽

Mediterranean Fever ◽

Exon 10

Background:Familial Mediterranean fever (FMF) is an autoinflammatory disease that is caused by Mediterranean fever (MEFV) gene mutations. It is characterized by recurrent and self-limiting febrile attacks within a short period. Although the pathologic significance ofMEFVexon 2 or exon 3 common variants in patients with FMF is modest and these variants are usually associated with less severe clinical presentations of FMF (1, 2), their combined effects with pathogenic mutation in exon 10 remain to be evaluated.Objectives:To determine the combined effect of common variants on clinical manifestations and inflammasome activity, we compared the clinical and laboratory characteristics between the coexistence and non-coexistence ofMEFVexon 2 or exon 3 variants in patients with FMF that had a heterozygousMEFVexon 10 mutation.Methods:We excluded patients with FMF that had twoMEFVexon 10 mutations in one or more alleles and those withMEFVvariants in exons other than in exons 2, 3, or 10. Finally, we reviewed 131 Japanese patients with FMF that had a heterozygousMEFVexon 10 mutation, and they were divided into the groups with and withoutMEFVexon 2 or exon 3 variants of 34 and 97, respectively. All enrolled patients had only a heterozygous M694I mutation in exon 10 of theMEFVgene. We measured serum IL-18 levels at remission without febrile attacks in the groups with and withoutMEFVexon 2 or exon 3 variants of 9 and 31, respectively.Results:In the univariate analysis, the group with variants in exon 2 or exon 3 had significantly earlier onset (16.0 years v.s. 20.5 years, p = 0.04), a higher percentage of thoracic pain with febrile attacks (68% v.s. 44%, p = 0.02), a higher frequency of attack (1.0/month v.s. 0.5/month, p = 0.02), and a higher IL-18 level in the serum at remission (606.3 pg/ml v.s. 168.4 pg/ml, p = 0.04, Figure 1) compared to the group without these variants. Importantly, multivariate analyses showed that the coexistence ofMEFVexon 2 or exon 3 variants and an exon 10 mutation was independently and significantly associated with earlier onset of FMF (p = 0.049) and thoracic pain (p = 0.03).Figure 1.Conclusion:Our results suggest that the coexistence ofMEFVexon 2 or exon 3 variants and aMEFVexon 10 mutation has combined effects on inflammasome activation in the Japanese population.References:[1]Migita K, Uehara R, Nakamura Y, et al. Familial Mediterranean fever in Japan. Medicine (Baltimore). 2012 Nov;91(6):337-43.[2]Shinar Y, Livneh A, Langevitz P, Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever. J Rheumatol. 2000;27(7):1703.Disclosure of Interests:None declared

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Familial Mediterranean fever-associated mutation pyrin E148Q as a potential risk factor for multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458512437813 ◽

2012 ◽

Vol 18 (9) ◽

pp. 1229-1238 ◽

Cited By ~ 11

Author(s):

T Kümpfel ◽

L-A Gerdes ◽

T Wacker ◽

A Blaschek ◽

J Havla ◽

...

Keyword(s):

Multiple Sclerosis ◽

Risk Factor ◽

Familial Mediterranean Fever ◽

Mefv Gene ◽

German Population ◽

Gene Group ◽

Mefv Mutations ◽

Mediterranean Fever ◽

Group 2 ◽

Group 1

Background: Familial Mediterranean fever (FMF) is an inherited autoinflammatory disease caused by mutations in the MEFV gene and characterized by recurrent febrile polyserositis. A possible association of FMF and multiple sclerosis (MS) has been suggested in cohorts from Turkey and Israel. Objective: The objective of this study was to investigate the prevalence of MEFV mutations in subjects with MS and in controls in Germany. Methods: One-hundred and fifty seven MS patients with at least one symptom or without symptoms suggestive of FMF from our outpatient clinic were investigated for mutations in exons 2, 3, and 10 of the MEFV gene (group 1). 260 independent MS patients (group 2) and 400 unrelated Caucasian controls (group 3) were screened selectively for the low-penetrance pyrin mutations E148Q and K695R Results: In group 1, 19 MS patients (12.1%) tested positive for a mutation in the MEFV gene, mainly the E148Q ( n=7) substitution. Fifteen of the 19 mutation-positive individuals reported at least one symptom suggestive of FMF. In three cases, we could identify additional family members with MS. In these pedigrees, the E148Q exchange co-segregated with MS ( p=0.026). Frequencies of the pyrin E148Q and K695R mutations were not statistically different between MS group 2 and controls but they occurred with a surprisingly high frequency in the German population. Conclusion: The MEFV gene appears to be another immunologically relevant gene locus which contributes to MS susceptibility. In particular, the pyrin E148Q mutation, which co-segregated with disease in three MS families, is a promising candidate risk factor for MS that should be further explored in larger studies.

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A new MEFV gene mutation in an Iranian patient with familial Mediterranean fever

Reumatismo ◽

10.4081/reumatismo.2019.1141 ◽

2019 ◽

Vol 71 (2) ◽

pp. 85-87

Author(s):

S. Farjadian ◽

F. Bonatti ◽

A. Soriano ◽

M. Reina ◽

A. Adorni ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Mutational Analysis ◽

Novel Mutation ◽

Present Report ◽

Case Reports ◽

Mefv Gene ◽

Recurrent Fever ◽

Iranian Patient ◽

Mediterranean Fever ◽

Exon 10

Familial mediterranean fever (FMF) is an inherited autoinflammatory disorder characterized by recurrent episodes of fever and painful inflammation involving the intra-abdominal organs, the lungs and the joints, which is highly prevalent in specific ethnic groups including the Iranians. We report a 12-year-old boy from Iran, with a clinical history of recurrent fever. Based on the suggestive clinical data, mutational analysis revealed the presence of the novel c.1945C>T heterozygous variant in exon 10, which leads to a leucine to phenylalanine change at position 649 of the protein. The mutation was inherited from the mother. This novel mutation lies in exon 10 of the MEFV gene, which encodes for a domain called B30.2-SPRY, located in the C-terminal region of the pyrin protein and contains the most frequent mutations associated with FMF. The present report expands the spectrum of MEFV gene mutations associated with FMF. The uniqueness of this study, compared with other published case reports, consists in the new mutation found in the MEFV gene. In fact, new mutations in this gene are of high interest, in order to better understand the role of this gene in autoinflammation.

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A novel insertion mutation identified in exon 10 of the MEFV gene associated with Familial Mediterranean Fever

BMC Medical Genetics ◽

10.1186/1471-2350-15-74 ◽

2014 ◽

Vol 15 (1) ◽

Cited By ~ 2

Author(s):

Hasan Dogan ◽

Fatih Akdemir ◽

Sener Tasdemir ◽

Omer Atis ◽

Eda Diyarbakir ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Mefv Gene ◽

Insertion Mutation ◽

Mediterranean Fever ◽

Exon 10

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Genetic Screening of Familial Mediterranean Fever in Japan.

Blood ◽

10.1182/blood.v108.11.3846.3846 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3846-3846

Author(s):

Yasuko Miyahara ◽

Kouhei Yamashita ◽

Takashi Miyoshi ◽

Akifumi Takaori ◽

Masataka Sasada ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Genetic Screening ◽

Large Scale ◽

Periodic Fever ◽

Mefv Gene ◽

Unknown Origin ◽

Polymorphonuclear Cells ◽

Exon 2 ◽

Mediterranean Countries ◽

Mediterranean Fever

Abstract There have been few reports of the patients with Familial Mediterranean Fever (FMF) in Japan, probably because FMF patients are preoccupied to be rare in Japan. We experienced 10 cases likely to be clinically diagnosed as FMF with periodic fever of unknown origin. FMF is an autosomal recessive disease resulting from the genetic mutations in the FMF gene (MEFV), which codes for a protein named Pyrin. Pyrin is expressed in mainly polymorphonuclear cells and monocytes and it is proposed that it regulates inflammation. The MEFV gene is located on chromosome 16p13.3 and comprises 10 exons. Several mutations in the MEFV gene have been identified, however the mutations are mostly located in exon 2 and 10. Therefore, we performed genetic screening of exon 2 and 10 in the 10 patient samples. The median age of the patients was 34 (17–49) years old. They are four males and six females. DNA was isolated from polymorphonuclear cells of the patients and PCR was performed with selective primers of exon 2 and 10 of MEFV gene, respectively. Thereafter, direct sequence of exon 2 and 10 of the PCR products was performed. As a result, the mutations of E148Q in exon 2 and M694I in exon 10, which are commonly observed in previous reports, were identified in seven and six out of 10 patients, respectively. All patients had either E148Q or M694I mutation. Three patients have both E148Q and M694I mutations. One 50-year-old female patient, who had a homozygous M694I mutation, suffered from severe renal AA amyloidosis. The mutation at M694 has been mostly reported as M694V, particularly in Mediterranean countries, however interestingly, all of the mutations of M694 were M694I, not M694V in our 10 Japanese patients. It is reported that healthy carrier frequency of the E148Q mutation was about 16% in Japan, so it is suggested that E148Q mutation may be profoundly involved in cause of disease, because E148Q mutation is observed among 70% of our patients. We herein report the unique genetic features of FMF patients in Japan. A further large scale of investigation would be necessary for confirming the significance of E148Q and M694I mutations in FMF patients in Japan.

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Effects of different Familial Mediterranean Fever gene mutations and in vitro Colchicine treatment on Peripheral Blood Mononuclear Cells production of IL-6

Bangladesh Journal of Medical Science ◽

10.3329/bjms.v12i4.16659 ◽

2013 ◽

Vol 12 (4) ◽

pp. 370-377

Author(s):

AK Daoud ◽

WH Rajab ◽

KM Alawneh ◽

MA Nizar Harfiel

Keyword(s):

Familial Mediterranean Fever ◽

Peripheral Blood Mononuclear Cells ◽

Mononuclear Cells ◽

Colchicine Treatment ◽

Peripheral Blood Mononuclear ◽

Exon 2 ◽

Blood Mononuclear Cells ◽

Mediterranean Fever ◽

Exon 10

Rationale: We wanted to study the effects of Familial Mediterranean Fever (FMF) genetic mutations in Northern Jordan population and in vitro Colchicine treatment on the peripheral blood mononuclear cells (PBMN) production of IL-6 as a marker of disease activity. Methods: - 17 FMF patients and 9 controls were studied. (4 patients had exon 10 mutations only (M680I and V726A), 5 patients had exon 2 mutations (R202Q and E148Q) only and 8 patients with both exon mutations (compound homozygous or heterozygous M694V and R202Q). PBMN cells were incubated with Lipopolysaccharide at 100ng/ml or colchicine 10 ng/ml alone or both. Results: The results showed higher IL-6 levels in the FMF group than control for all treatment modalities, (108.97 vs. 56.49 ng/ml for unstimulated cells) with the highest levels when both exons are involved. Exon 10 mutations were associated with a higher IL-6 level than exon 2 mutations only. Exon 2 mutations alone also were associated with a higher than control IL-6 levels suggesting that it is not a polymorphism phenomenon and is involved in the pathogenesis. In vitro Colchicine treatment caused an increase in the production of IL-6 - although not as high as with LPS - for all groups. Conclusions: Mutations occurring in exon 10 are more significant than mutations occurring in exon 2, although both are contributing to the disease. However colchicine was associated with a paradoxical increase in IL-6 levels. This observation needs confirmation with different colchicine levels in the culture medium and warrants thinking about its exact mechanism of action. DOI: http://dx.doi.org/10.3329/bjms.v12i4.16659Bangladesh Journal of Medical Science Vol. 12 No. 04 October 13 Page 370-377

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Idiopathic Uveitis and Familial Mediterranean Fever: Is There Any Relationship?

Autoimmune Diseases ◽

10.1155/2014/238931 ◽

2014 ◽

Vol 2014 ◽

pp. 1-3 ◽

Cited By ~ 3

Author(s):

Farhad Salehzadeh ◽

Ozra Yasrebi ◽

Mahsa Hosseini Khotbesara ◽

Maryam Hosseini Khotbesara

Keyword(s):

Familial Mediterranean Fever ◽

Inflammatory Process ◽

Mefv Gene ◽

Gene Mutations ◽

The Other ◽

Blurred Vision ◽

Mefv Mutations ◽

Auto Inflammatory Disease ◽

Mediterranean Fever ◽

Positive Results

Introduction. Familial Mediterranean fever (FMF) is an auto-inflammatory disease characterized by attacks of fever and polyserositis. FMF is often associated with other autoimmune diseases such as rheumatoid arthritis, polyarteritis nodosa (PAN), and Behcet. Uveitis is an inflammatory process caused by underlying infectious and inflammatory disorders. This study investigates the probable relationship between idiopathic uveitis and FMF.Methods. Patients with idiopathic uveitis were analyzed for the 12 most common MEFV mutations (P369S, F479L, M680I(G/C), M680I(G/A), I692del, M694V, M694I, K695R, V726A, A744S, R761H, E148Q) by a reverse hybridization assay (FMF StripAssay,Vienna lab,Vienna, Austria).Results. 12 patients with idiopathic uveitis were enrolled in this study. 10 of them were female. The youngest patient was a 7-year-old child and the oldest was 57. The most common complaints of patients were blurred vision and then eye redness. One patient was heterozygous for R761H. Genetic analysis of the 12 most common MEFV mutations in the patients with idiopathic uveitis didnot have any positive results.Conclusion. According to the analysis of the 12 most common MEFV gene mutations, FMF is not an underlying cause of idiopathic uveitis. On the other hand, uveitis merely could not be the first presentation of FMF.

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Longitudinal analysis of serum interleukin-18 in patients with familial Mediterranean fever carrying MEFV mutations in exon 10

Cytokine ◽

10.1016/j.cyto.2017.10.007 ◽

2018 ◽

Vol 104 ◽

pp. 143-146 ◽

Cited By ~ 4

Author(s):

Taizo Wada ◽

Tomoko Toma ◽

Hanae Miyazawa ◽

Eiko Koizumi ◽

Tetsujiro Shirahashi ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Longitudinal Analysis ◽

Interleukin 18 ◽

Mefv Mutations ◽

Mediterranean Fever ◽

Exon 10

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Presentation of a new mutation in FMF and evaluating the frequency of distribution of the MEFV gene mutation in our region with clinical findings

Molecular Biology Reports ◽

10.1007/s11033-020-06040-y ◽

2021 ◽

Vol 48 (3) ◽

pp. 2025-2033

Author(s):

Abdullah Arpacı ◽

Serdar Doğan ◽

Hazal Fatma Erdoğan ◽

Çiğdem El ◽

Sibel Elmacıoğlu Cura

Keyword(s):

Familial Mediterranean Fever ◽

Ethnic Groups ◽

Gene Mutation ◽

Mefv Gene ◽

Gene Mutations ◽

University Hospital ◽

New Mutation ◽

Exon 2 ◽

Mediterranean Fever ◽

Mefv Gene Mutation

AbstractFamilial Mediterranean Fever (FMF), which is an autosomal recessive disease characterized by recurrent self-limiting fever, peritonitis, pleuritis, arthritis and erysipelas-like erythemas, has been common among ethnic groups such as Turkish, Armenian, Arabic and Jewish. The clinical presentation is caused by mutations in the MEFV gene encoding the Pyrin protein. In this study, we aimed to present a new mutation that has not been previously defined from the mutations in the MEFV gene which is responsible for the genetic pathology of familial Mediterranean fever and to evaluate the frequency of distribution of the MEFV gene mutation among different ethnic groups living in our region. In present retrospective study, a total of 2639 clinically suspected FMF patients who were referred to Hatay Mustafa Kemal University Hospital between 2010 and 2017 were recorded. MEFV gene mutations were observed using DNA sequence analysis. MEFV mutations were found in 2079 of the 2639 patients (78.7%) Among these patients 184 (6.97%) were homozygous, while 1365 (51.72%) were heterozygous. The most frequently observed mutation was R202Q (1319, 19.55%) followed by E148Q (n = 476, 7.05%), M694V (n = 439, 6.51%), V726A (n = 146, 2.16%) and M680I (n = 135, 2%). In a case clinically diagnosed as FMF, a new mutation called S145G (p. Ser145Gly, c.433A > G) was identified in exon 2 of the MEFV gene. Besides, addition of a new pathogenic MEFV variant to the literature, the relationship between the FMF clinic and homozygous form of R202Q, which was previously considered as a polymorphism, was highlighted.

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