Accueil > Recherche > Équipe J. Boucraut > Modeling molecular mechanisms underlying familial dysautonomia (...)

Modeling molecular mechanisms underlying familial (...)

Familial dysautonomia (FD) is the third type of a group of very rare hereditary diseases affecting the development and the survival of peripheral sensory and autonomous neurons. In 2001, the major mutation causing FD has been identified as the replacement of a thymine by a cytosine at the 6th base of IKBKAP gene intron 20. Such mutation induces an alternative splicing of pre-messenger RNA and results in exon 20 skipping with a high frequency in the nervous system. Our first investigations helped us to understand why the FD mutation induces mRNA alternative splicing, however, we still ignore how the tissue-specificity of such alternative splicing is established (Ibrahim et al, 2007 ; Hims et al, 2007). Therefore, in collaboration with Prof F Axelrod (NYU School of Medicine, New York , USA), we devised an original model, based on olfactory ecto-mesenchymal stem cells (OE-MSCs), expanded from nasal biopsies of control and FD patients, to recapitulate the steps during which IKBKAP mRNA alternative splicing is regulated (Boone et al, 2010). Such a model also allow us, in collaboration with the groups of Dr C Nguyen (TAGC-INSERM U1090, Marseille-Luminy) and Prof J Gabert (Transcriptome facility, North Marseille Medical School) to study the signaling pathways aletered in FD cells, by performing the transcriptome analysis of FD cells during neuro-glial differenciation or after addition of drugs that restore a correct splicing of IKBKAP (Boone et al, 2012). Deciphering the molecular mechanisms behind FD progression should help in proposing alternative therapeutics to stop neurodegenertion in FD specifically but also represents a proof of principle for a strategy adapted to many other genetic diseases affecting the nervous system.


2012 : Familial Dysautonomia Foundation : 50000 dollars grant award

2012 : Association Française contre les Myopathies (AFM) : 49000 euros on the project « Understanding splicing defects underlying familial dysautonomia »

2008 : Association Française contre les Myopathies (AFM) : 44000 euros on the project « Understanding exon skipping to cure familial dysautonomia »

    Ils nous font confiance

  • logo amu
  • logo cnrs
  • logo inserm
  • logo AP-HM
  • logo F�d�ration pour la Recherche sur le Cerveau
  • logo Fondation pour la Recherche Medical en France
  • logo IBiSA
  • logo Europe programme FEDER
  • logo Agence Nationale de la Recherche
  • logo Plateforme Technologique Aix-Marseille
  • logo Vect-Horus
  • logo Neuron Experts