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Identification De Nouveaux Gènes D'ataxies Récessives

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Identification De Nouveaux Gènes D'ataxies Récessives Institut de Génétique et de Biologie Moléculaire et Cellulaire CNRS - INSERM - Université de Strasbourg Ecole Doctorale des Sciences de la Vie et de la Santé THESE Pour l’obtention du grade de Docteur de l’Université de Strasbourg Discipline: Sciences du Vivant Aspects moléculaires et cellulaires de la biologie Par Mirna Assoum Identification de nouveaux gènes d’ataxies récessives: implication de la mitochondrie et de nouvelles voies physiopathologiques Soutenue publiquement le 10 Novembre 2010 devant la commission d’examen: Mr Le Professeur Michel Koenig Directeur de Thèse Mr Le Professeur Nicolas Lévy Rapporteur externe Mme Le Dr. Jamilé Hazan Rapporteur externe Mr Le Professeur Stéphane Viville Rapporteur interne Remerciements Je remercie tout d’abord les Professeurs Nicolas Lévy et Stéphane Viville et le Dr. Jamilé Hazan de me faire l’honneur de participer à ce jury de thèse. J’exprime toute ma reconnaissance au Professeur Michel Koenig de m’avoir accueillie dans son équipe. Je le remercie de m’avoir initiée à la recherche et de m’avoir guidée pendant ces 5 années. Je tiens à lui exprimer toute ma reconnaissance pour tout ce qu’il m’a appris et pour sa patience, son enthousiasme de me communiquer toutes ses connaissances en Génétique Humaine. Je remercie chaleureusement le professeur Jean-Louis Mandel pour m’avoir accueillie dans l’équipe de Génétique Humaine Strasbourgeoise. Je le remercie pour ses conseils et ses discussions scientifiques. Je remercie tous nos collaborateurs cliniciens et généticiens pour leur contribution dans tout ce travail. J’exprime toute ma reconnaissance aux patients et à leurs familles. Un grand merci aux services communs de l’IGBMC : l’équipe des puces (Christelle Thilbaut....) ; l’ancienne plateforme de séquençage (Serge, Ingrid) ; service de culture cellulaire, service des peptides, service des anticorps et microscopie. Je tiens à remercier le CNRS d’avoir financé mes 3 premières années de thèse, l’IGBMC et l’AFM pour ma 4ème année de thèse. Je emercie l’IGBMC pour nous offrir ce contexte international. Je remercie chaleureusement Nathalie Drouot pour son aide et sa patience. Je remercie les membres anciens «Ataxies récessives» pour leur amitié et collaboration; Clotilde de m’avoir initiée pendant mon stage de Master 2. Je te remercie pour ta patience durant mon Master2. Merci pour les quelques photos que tu m’envoies de temps à autre des états-unis. Je pense que nous nous croiserons quand tu seras de retour en France. Je remercie Mathieu et Moez. Moez, je pense que je te croiserai toujours dans les congrès de génétique. Je remercie Dorra pour son amitié, sa gentillesse, ses conseils. Je suis contente pour la naissance du petit Moncef. Je remercie tous les membres passés et présents de l’équipe Génétique Humaine pour leur amitié et leur soutien pendant toutes ces années. Merci à mims pour son sourire chaleureux, Merci à tous les membres de l’équipe PolyQ, l’équipe MTM (tellement nombreux que je ne peux pas les citer tous bien que je les apprécie), l’équipe XFRA, l’équipe retard mental. Je remercie tous ceux qui m’ont aidé de près ou de loin durant ma thèse surtout au niveau technique. Je remercie chaleureusement Karim pour son amitié, sa compagnie, les discussions scientifiques et ses conseils. Je remercie Lama pour son amitié, son grand cœur, son soutien et son aide pour moi à mon arrivée à Strasbourg. Merci à mes voisins Friedreich : Florent car je pense que tu m’as supportée avec ma musique arabe de tous les matins!! Bon, je t’ai aussi supporté pendant ces années. Un grand merci à Laurence pour m’avoir initié à la culture cellulaire. Merci à Alain pour la stratégie de clonage. Merci à Marie, Stéphane, Nadège Calmels, Nadège Vaucamps, Floriana et Julia et les autres pour leurs conseils et leur amitié. Merci à Marina pour son amitié et son soutien. Je remercie christine Ayoub pour son amitié, son soutien et tous les bons moments que nous avons passés à Strasbourg. Je remercie mes compatriotes libanais, en particulier Elias qui m’a supportée pendant la rédaction de ma thèse. Un grand merci à Alice, Rita et Anastasia pour leur amitié et leur soutien. Merci à Soraya pour son soutien, sa présence et son aide précieuse. Merci à Ghada, Nada et leurs maris. Je remercie Soumiya et Axelle, pour leur amitié. Je remercie ma famille pour m’avoir soutenue pendant les six années passées en France. Je remercie mon père pour m’avoir toujours encouragée à poursuivre dans la recherche et à découvrir de nouveaux horizons. Désolée si j’ai oublié d’autres personnes mais sachez que vous comptez pour moi. Table des matières Liste des abréviations .............................................................................................................................. 6 Liste des Figures ...................................................................................................................................... 8 Liste des tableaux .................................................................................................................................... 9 Introduction ........................................................................................................................................... 10 I. Les ataxies........................................................................................................................................... 12 A. Aperçu général .............................................................................................................................. 12 B. Les caractéristiques cliniques et génétiques des ataxies ............................................................... 14 1. Les ataxies dominantes .............................................................................................................. 14 2. Ataxies récessives dégénératives ................................................................................................... 16 a. Protéines mitochondriales et stress oxydant ................................................................................ 16 a.1. Ataxie de Friedreich ............................................................................................................... 17 a.2. Ataxie spinocérébelleuse avec anémie sidéroblastique liée à l’X .......................................... 19 a.3. Ataxie avec déficit en vitamine E ........................................................................................... 20 a.4. Abetalipoprotéinémie ............................................................................................................. 21 a.5. L’ataxie spino-cérébelleuse de début infantile ....................................................................... 22 a.6. SANDO et MIRAS: mutations de l’ADN polymérase mitochondriale POLG ...................... 24 a.7. La maladie de Refsum ............................................................................................................ 25 b. Réparation de l’ADN ..................................................................................................................... 26 b.1. L’Ataxie Télangectasie ........................................................................................................... 26 b.2. L’ataxie télangectasie-like ...................................................................................................... 28 b.3. L’ataxie avec Apraxie Oculomotrice de type 1 ...................................................................... 29 b.4. L’ataxie avec Apraxie Oculomotrice de type 2 ...................................................................... 31 b.5. L’ataxie cérébelleuse avec neuropathie de type 1 .................................................................. 33 c. Autres mécanismes moléculaires ................................................................................................... 33 1 c.1. Ataxie spastique autosomique récessive du Charlevoix-Saguenay ........................................ 33 c. 2. Le syndrome de Marinesco-Sjögren ...................................................................................... 34 c.3. Ataxie cérébelleuse autosomique récessive de type 1 ............................................................ 35 c.4. Syndrome ataxie/tremblement associés à l’X Fragile (FXTAS) ............................................ 35 II. Les paraplégies spastiques héréditaires ............................................................................................ 39 A. Physiopathologie des PSH ............................................................................................................ 39 A.1. Dysfonctionnement Mitochondrial dans les paraplégies spastiques héréditaires ...................... 40 A.1.1. SPG7 ................................................................................................................................... 40 A.1.2. SPG13 ................................................................................................................................. 41 A.1.3. SPG31 ................................................................................................................................. 41 A.2. Trafic vésiculaire et transport axonal ........................................................................................ 41 A.2.1.SPG4 .................................................................................................................................... 42 A.2.2. SPG3A ...............................................................................................................................
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