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Reduced MEFV messenger RNA expression in patients with familial Mediterranean fever
Cécile Notarnicola1, Marie-Noëlle Didelot, Isabelle Koné-Paut
1Laboratoire de Génétique Moléculaire et Chromosomique, Hôpital Arnaud de Villeneuve, 371 Avenue du Doyen Gaston Giraud, 34295 Montpellier Cedex 5, France.
Objective:
Familial Mediterranean fever (FMF) is the most common inherited periodic syndrome. The disease phenotype and the almost exclusive expression of the causative gene, MEFV, in leukocytes suggest that this gene plays an important role in the inflammatory cascade. Since most of the known mutations are conservative, we sought to determine how minor DNA defects can give rise to the dramatic phenotypic features seen in FMF.
Methods:
To address whether the molecular basis of the phenotype-genotype correlation could be related to altered MEFV messenger RNA (mRNA) expression, we quantified the relative abundance of MEFV transcripts in peripheral blood leukocytes from patients with FMF, healthy carriers of a single MEFV mutation, and healthy control subjects.
Results:
We found significantly lower expression of MEFV mRNA in genetically ascertained FMF patients than in healthy controls (0.7 versus 1.1; P = 0.00001). In healthy carriers, the mRNA levels were intermediate, suggesting a true dose-response relationship between the number of mutations and the abundance of MEFV transcripts. The difference between healthy controls and healthy carriers was significant (1.1 versus 0.8; P = 0.008), demonstrating that the decrease in mRNA expression is related to a molecular defect independent of FMF symptoms. MEFV mRNA expression was also found to be a function of the type of mutations. The lowest MEFV levels were found in healthy carriers and patients with M694V. Moreover, we observed an inverse correlation with the clinical severity score (r = -0.6, P = 0.04 and r = -0.6, P = 0.004 in patients with 1 and 2 M694V mutations, respectively).
Conclusion:
Our results demonstrate that MEFV message levels are related to both the genotype and the phenotype, and suggest that the pathophysiology of FMF relies on a quantitative defect of MEFV mRNA expression.
Insights
Familial Mediterranean fever (FMF) is linked to reduced MEFV gene expression. Lower MEFV mRNA levels correlate with disease severity and specific mutations, suggesting a quantitative defect in FMF.
Area of Science:
- Genetics
- Immunology
- Molecular Biology
Background:
- Familial Mediterranean fever (FMF) is an inherited periodic syndrome.
- The MEFV gene, primarily expressed in leukocytes, is implicated in FMF pathogenesis.
- Understanding how minor DNA defects cause FMF's dramatic phenotype is crucial.
Purpose of the Study:
- To investigate the relationship between MEFV gene expression and FMF phenotype.
- To determine if altered MEFV messenger RNA (mRNA) levels explain genotype-phenotype correlations in FMF.
Main Methods:
- Quantified relative MEFV mRNA abundance in peripheral blood leukocytes.
- Compared expression levels in FMF patients, healthy carriers, and healthy controls.
Main Results:
- FMF patients exhibited significantly lower MEFV mRNA expression than controls.
- Healthy carriers showed intermediate levels, indicating a dose-response relationship.
- MEFV mRNA levels varied by mutation type (e.g., M694V) and inversely correlated with clinical severity.
Conclusions:
- MEFV mRNA levels are associated with both genotype and phenotype in FMF.
- The pathophysiology of FMF may involve a quantitative defect in MEFV mRNA expression.