title: Reduced MEFV messenger RNA expression in patients with familial Mediterranean fever.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratoire de Génétique Moléculaire et Chromosomique, Hôpital Arnaud de Villeneuve, 371 Avenue du Doyen Gaston Giraud, 34295 Montpellier Cedex 5, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Notarnicola
authors.forename: Marie-Noëlle
authors.initials: MN
authors.lastname: Didelot
authors.forename: Isabelle
authors.initials: I
authors.lastname: Koné-Paut
authors.forename: Fabienne
authors.initials: F
authors.lastname: Seguret
authors.forename: Jacques
authors.initials: J
authors.lastname: Demaille
authors.forename: Isabelle
authors.initials: I
authors.lastname: Touitou
mesh_terms: D000328:Adult; D003598:Cytoskeletal Proteins; D010505:Familial Mediterranean Fever / Q000235:genetics* / Q000503:physiopathology*; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D009000:Monocytes / Q000502:physiology; D009154:Mutation; D009504:Neutrophils / Q000502:physiology; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D000071198:Pyrin; D012333:RNA, Messenger / Q000378:metabolism; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index
chemical_list: D003598:Cytoskeletal Proteins; C000604192:MEFV protein, human; D011506:Proteins; D000071198:Pyrin; D012333:RNA, Messenger