Ces travaux de cohortes de patients au phénotype du syndrome de Noonan et du syndrome LEOPARD ont permis de participer à la découverte de l‟implication d‟une voie de signalisation cellulaire dont l‟origine génétique est maintenant démontrée.
Les résultats de nos travaux réalisés depuis 2002 auront permis, avec les équipes travaillant sur le même sujet, d‟orienter les investigations et les nouveaux projets de recherche qui étudient spécifiquement le rôle du gène
PTPN11 dans l‟embryologie du cœur. Du fait de l‟hétérogénéité génétique mise en évidence au fil des études, les travaux de plusieurs équipes internationales ont permis de détailler les phénotypes et de les répertorier en un spectre connu sous l‟acronyme « NCFC » ou syndromes « neuro - cardio - facio - cutanés». Les mutations génétiques et les voies de signalisation ainsi modifiées exercent des effets spécifiques au cours du développement embryonnaire sur une structure particulière, voire sur les interactions d‟organes et de systèmes. Elles sont responsables d‟effets précis en terme de biologie cellulaire démontrés in vitro chez les orthologues mais partiellement étudiables ou confirmés in vivo et chez l‟humain. Les mutations identifiées sont toujours des mutations „faux sens‟ mais selon leur nature, elles ont été démontrées être responsables, in vitro, soit d‟un accroissement de l‟activation de la phosphatase (effet „gain de fonction‟), soit d‟une diminution de cette activation (effet „dominant négatif‟). À partir de l‟orthologue de la Drosophile csw, hétérozygote pour une mutation à effet dominant négatif, il est maintenant montré que l‟effet de l‟allèle mutant, sur le plan fonctionnel, est responsable in vivo d‟un effet „gain-de-fonction‟.
Les résultats des différents travaux accomplis autorisent le développement de programmes de recherche et la mise sur pied d‟études qui vont analyser, au
niveau cellulaire, les effets des mutations du gène sur le développement des dysrythmies et des troubles de la conduction cardiaque (pace-maker, cardiomyocytes).
Des projets d‟études et des études collaboratives, à l‟échelon national et international, sont en cours d‟élaboration et de réalisation afin :
1) de constituer des grandes cohortes de patients autorisant des descriptions phénotypiques et des caractérisations de génotypes précis 2) d‟analyser les mutations impliquées chez les patients porteurs de
mutation au sein du gène SOS1 et développant des tumeurs de type rhabdomyosarcome
3) de développer des modèles permettant d‟étudier les effets des mutations de ces gènes (études d‟expression)
4) d‟explorer les effets, au niveau cellulaire, d‟agents modulateurs et/ou inhibiteurs de la voie RAS (exemple : inhibiteur de la farnésyltransférase R115777 ou Zarnestra®)(Caraglia 2007, Chen L. 2006)
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