Autoinflammatory diseases unit
French National referral centre
Biology-Pathology research pole - University Hospital of Montpellier

   

 
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Familial Mediterranean Fever overview

  • Autosomal recessive transmission
  • Commonly found in Mediterranean populations
  • Associates fever, serositis, erysipelas, amyloidosis (if not treated)
  • Triggering factors unknown
  • Massive influx of neutrophils to the site of inflammation
  • Most efficient treatment: colchicine in 95% of cases
  • The gene MEFV
    • Discovered in 1997 by our consortium PubMed
    • Expressed mainly in neutrophils and monocytes
  • encodes protein Marenostrine/Pyrine (M/P) which regulates inflammation via the inflammasome through mechanisms yet to be determined

 

 

 

 

 

Physiopathology of FMF


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Our initial results

  • Identification of the gene
  • Phenotype-genotype correlations
  • Links with multifactorial AIDs
  • Expression of M/P and cytokines
Our work up to 2002 allowed us to:
  • identify the FMF gene (MEFV) within a consortium PubMed
  • define genotype-phenotype correlations PubMed
  • evaluate risk factors of renal amyloidosis PubMed
  • uncover MICA as the first genetic modifier locus PubMed
  • confirm that MEFV is implicated in multifactorial AIDs as a factor determining
    • susceptibility to Behçet PubMed
    • severity for Crohn's PubMed
  • show a decrease in the level of expression of MEFV PubMed
  • show an increase in cytokines IL-6 and IL-8 in these patients PubMed

 


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Our recent results onMEFV

  • Promotor-regulating elements
  • Post-transcriptional regulation by NMD

Study of the gene promotor region PubMed

  • We have found 6 new sequence variants in the region localised upstream of ATG in patients affected by FMF who present no mutation in the coding sequence.
  • We have characterised the promoter and hence determined that the region localised between nucleotides -949 and -152 of the initiator codon is important in the regulation of the expression and contains an activator region localised between nucleotides -571 and -414.
  • The activity of the promoter containing the variants c-614C>G and c-381C>T decreases by 70 to 100 % respectively, by comparison with the normal sequence (in vitro luciferase assay)

 

Post-transcriptional regulation analysis PubMed

New splice variants: We have identified 5 new alternative splice variants by RT-PCR on mRNAs from the blood leukocytes of 60 patients and 34 controls (no difference in terms of distribution).

Role of the nonsense-mediated decay (NMD): Alternative splicing and NMD are often coupled together in the post transcriptional regulation of gene expression.
We showed that the gene MEFV is the first autoinflammatory gene regulated by NMD, an event which occurs in a cell and transcript dependent manner.

Hypothesis on the M/P variants translated:

  • Different M/P products would explain the controversies surrounding its function in inflammation
  • The efficiency of NMD could play a role of phenotypic modifier in the physiopathology of FMF
  • The regulation of expression of MEFV is more complex than originally anticipated

 

Our projects

Rationale: Programmed cell death or apoptosis is increased in monocytes and neutrophils after induction by pathogen-associated molecular patterns specific to the bacterium E. coli, whereas phagocytosis by monocytes of patients is reduced.

Questions: How is M/P involved in and how does Colchicine affect the resolution of inflammation achieved by monocytes/macrophages?

  1. Phagocytosis of the danger signal?
  2. Cell death of the monocytes/macrophages?
  3. Phagocytosis of apoptotic cells by macrophages?

Objective: We propose to characterise in vitro the function of protein variants of the gene MEFV in the resolution of the inflammation with the aim of understanding why these steps are deficient in patients with FMF.

Contact : Dr Sylvie Grandemange

 
Réalisé par Florian Milhavet   |   Mentions légales   |   Contact & Plan d'accès