תרומתי לרפואה

תורשה של FMF ושל עמילואידוזס

עבודות מחקר בנושא גנטיקה של FMF ועמילואידוזס ניתן למצוא ברשימת המאמרים המלאה, במאמרים הבאים: 136, 160, 201, 202, 212, 216, 219, 231, 260, 263, 269, 275, 293, 301, 309,  355, 369, 372, 377, 406, 407, 428, 429, 438, 442, 461, 463, 476, 519. (לרשימת המאמרים המלאה). להלן, מובאים תקצירים של 6 מאמרים נבחרים:

1. Amyloid. 1999 Mar;6(1):1-6.
MEFV mutation analysis in patients suffering from amyloidosis of familial Mediterranean fever.
Livneh A, Langevitz P, Shinar Y, Zaks N, Kastner DL, Pras M, Pras E. 

Abstract
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

2. Eur J Hum Genet. 2001 Mar;9(3):191-6.
A single mutated MEFV allele in Israeli patients suffering from familial Mediterranean fever and Behçet's disease (FMF-BD).
Livneh A, Aksentijevich I, Langevitz P, Torosyan Y, G-Shoham N, Shinar Y, Pras E, Zaks N, Padeh S, Kastner DL, Pras M.

Abstract
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 Behçet'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.

3. Am J Med Genet. 2001 Aug 15;102(3):272-6.
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.
Kogan A, Shinar Y, Lidar M, Revivo A, Langevitz P, Padeh S, Pras M, Livneh A.

Abstract
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.
 

4. Rheumatology (Oxford). 2007 Nov;46(11):1718-22. 
Unique spectrum of MEFV mutations in Iranian Jewish FMF patients--clinical and demographic significance.
Shinar Y, Kuchuk I, Menasherow S, Kolet M, Lidar M, Langevitz P, Livneh A.

Abstract
OBJECTIVES: To determine the spectrum of mutations in the Mediterranean fever gene (MEFV) of Iranian Jews with familial Mediterranean fever (FMF) and to analyse their clinical manifestations.
METHODS: FMF patients with both parents of Iranian-Jewish (IJ) extraction or with one IJ parent (IJ-other, 10 of each) were characterized for clinical manifestations, and the B30.2 (PRYSPRY) domain of their MEFV was sequenced for mutations.
RESULTS: Only one rare mutation, R653H, and one new mutation, G632S were present in the IJ group (in 2/10 patients), whereas the new, and common mutations were present in the IJ-other patients (8/10 patients). The new mutation was traced thrice to an IJ ancestor, and although carried asymptomatically by family members, it was over-represented in the patients (3/28 unrelated IJ alleles) compared non-affected IJ subjects (1/126 alleles, P = 0.03) or with non-Jewish Iranians (0/108 alleles, P = 0.001). The mutation was associated with a distinct phenotype regarding sites involved in the attack (P = 0.001), mild severity, sole expression of febrile episodes (P = 0.01) and a male bias (P = 0.01). In two 3D PRYSPRY models the G632S mutation was localized to a surface loop and close to a putative binding site.
CONCLUSIONS: Iranian Jews with FMF have a unique spectrum of mutations including a newly described mutation with a non-typical phenotype.

5. Arthritis Rheum. 2009 Jun;60(6):1862-6. 
Clinical disease among patients heterozygous for familial Mediterranean fever.
Marek-Yagel D, Berkun Y, Padeh S, Abu A, Reznik-Wolf H, Livneh A, Pras M, Pras E.

Abstract
OBJECTIVE: To define the molecular basis of familial Mediterranean fever (FMF) in patients with only 1 mutation in the MEFV gene.
METHODS: Genetic analysis was performed in 20 FMF patients, including full sequencing of complementary DNA (cDNA) samples and multiplex ligation-dependent probe amplification analysis. In patients with first-degree relatives with FMF, haplotype analysis was also performed.
RESULTS: A second mutation was found in 2 patients. In the other 18 patients, we could not identify additional mutations, large genomic deletions, or duplications. Analysis of single-nucleotide polymorphisms along the cDNA ruled out a lack of expression of 1 of the alleles. In 2 of the 3 families in which more than 1 sibling had FMF, we showed that the affected siblings inherited a different MEFV allele from the parent who did not have the MEFV mutation.
CONCLUSION: These findings are highly consistent with the existence of a clinical phenotype among some patients who are heterozygous for FMF and could explain the vertical transmission in some families. A single mutation in the MEFV gene may be much more common than was previously thought and may include up to 25% of patients who are diagnosed as having FMF.

6. Gene. 2012 Jan 10;491(2):260-3. 
The relative contribution of environmental and genetic factors to phenotypic variation in familial Mediterranean fever (FMF).
Ben-Zvi I, Brandt B, Berkun Y, Lidar M, Livneh A.

Abstract
INTRODUCTION: Familial Mediterranean fever (FMF) is an autosomal recessive disease, caused by mutations in the FMF gene MEFV (MEditerranean FeVer). It has a large phenotypic diversity even in patients with similar genotypes. Despite evidence that environmental factors (EFs) and genetic factors, including MEFV mutations (such as M694V, E148Q) and background modifier genes (MGs), affect the clinical manifestations of FMF, the relative contribution of each remains unknown.
METHODS: To investigate the relative contribution of environmental and genetic factors to the phenotype of FMF, we compared the intra-pair clinical concordance of 10 mono and 7 dizygotic twins with FMF. The part played by EFs was determined by the phenotypic discordance of the monozygous twins, and the MGs effect was determined by deducing the environmental effect, computed for MZ twins, from the phenotypic discordance of the dizygous twins.
RESULTS: The mean±SD of intra-pair concordance was higher in the MZ than in DZ twin group (88.1±13.2 vs. 70.7±14.1 respectively, P value<0.05). Based on the concordance in clinical manifestations in MZ and DZ twins, the environmental effect on the phenotype of FMF is estimated as 11.9%±6.6% and the MGs effect as 17.4%±15.5% in average.
CONCLUSIONS: In FMF the phenotype is affected by MEFV mutations, MGs and EFs in an estimated ratio of about 6:1.5:1 respectively.

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