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Apport De L'analyse Chromosomique Sur Différents Microréseaux D'adn Dans L'identification De Nouvelles Mutations E

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Apport De L'analyse Chromosomique Sur Différents Microréseaux D'adn Dans L'identification De Nouvelles Mutations E Apport de l’analyse chromosomique sur différents microréseaux d’ADN dans l’identification de nouvelles mutations et la caractérisation de gènes candidats impliqués dans la déficience intellectuelle Minh Tuan Huynh To cite this version: Minh Tuan Huynh. Apport de l’analyse chromosomique sur différents microréseaux d’ADN dans l’identification de nouvelles mutations et la caractérisation de gènes candidats impliqués dans ladéfi- cience intellectuelle. Médecine humaine et pathologie. Université de Lorraine, 2013. Français. NNT : 2013LORR0129. tel-01750122 HAL Id: tel-01750122 https://hal.univ-lorraine.fr/tel-01750122 Submitted on 29 Mar 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. AVERTISSEMENT Ce document est le fruit d'un long travail approuvé par le jury de soutenance et mis à disposition de l'ensemble de la communauté universitaire élargie. Il est soumis à la propriété intellectuelle de l'auteur. Ceci implique une obligation de citation et de référencement lors de l’utilisation de ce document. D'autre part, toute contrefaçon, plagiat, reproduction illicite encourt une poursuite pénale. Contact : [email protected] LIENS Code de la Propriété Intellectuelle. articles L 122. 4 Code de la Propriété Intellectuelle. articles L 335.2- L 335.10 http://www.cfcopies.com/V2/leg/leg_droi.php http://www.culture.gouv.fr/culture/infos-pratiques/droits/protection.htm Ecole doctorale BioSE (Biologie-Santé-Environnement) THESE Présentée et soutenue publiquement pour l’obtention du titre de DOCTEUR DE L'UNIVERSITE DE LORRAINE Mention : « Science de la Vie et de la Santé » Par MINH TUAN HUYNH Apport de l’analyse chromosomique sur différents microréseaux d’ADN dans l’identification de nouvelles mutations et la caractérisation de gènes candidats impliqués dans la déficience intellectuelle Le 15 Novembre 2013 Membres du jury: Rapporteurs : Monsieur le Professeur Jean-Luc BRESSON Biologie du développement et de la reproduction Université de Franche-Comté Madame le Professeur Dominique GAILLARD Génétique Université de Reims Champagne Ardennes Examinateurs : Monsieur le Professeur Bruno LEHEUP Génétique, Université de Lorraine Monsieur le Professeur Philippe JONVEAUX Génétique, Université de Lorraine (Directeur de thèse) --------------------------------------------------------------------------------------------------------------------------------------------- INSERM U954-Université de Lorraine Laboratoire de génétique-CHU de Nancy, rue du Morvan, 54511 Vandœuvre lès Nancy Remerciements Je tiens à remercier ici : Monsieur le Professeur Philippe JONVEAUX, mon directeur de thèse : un grand remerciement pour sa direction, son précieux encadrement tout au long de mon travail, son encouragement, sa bienveillance afin que je puisse finir mon projet à terme. Madame le Professeur Dominique GAILLARD et à Monsieur le Professeur Jean-Luc BRESSON pour l’honneur qu’il m’ont fait en acceptant d’évaluer ce travail, et d’être rapporteur de thèse. Monsieur le Professeur Bruno LEHEUP d’avoir accepté d’examiner mes travaux et pour son intérêt et son soutien chaleureux au sein de notre équipe de recherche. Madame le Docteur Céline Bonnet pour son aide et son encadrement sur le plan technique et scientifique, en particulier, la technique de l'analyse chromosomique sur microréseau d’ADN. Madame le Docteur Mylène Béri pour son encadrement et son aide au début lorsque je suis venu au labo. Merci de m'avoir aidé sur l'analyse chromosomique sur microréseau d’ADN. Madame le Docteur Mydriam Bronner pour la technique de séquençage de Sanger et le séquençage à haut débit ainsi que la technique de HRM (High Resolution Melting). Monsieur le Docteur Christophe Philippe pour la biologie moléculaire. Emmanuel Bresso pour les données bioinformatiques et les médecins généticiens cliniciens et neuropédiatres du CHU de Nancy, et des autres CHU qui ont contribué à notre travail de recherche. Un grand remerciement à toute l'équippe du laboratoire de génétique : à toutes celles et ceux qui m'ont accompagné dans ce travail, m'ont encouragé et ont mis toutes leurs compétences et leur savoir à profit pour faire avancer mon travail. Merci pour leur disponibilité de tous les instants. Table des matières REMERCIEMENTS........................................................................................................................2 TABLES DES FIGURES.................................................................................................................7 LISTE DES TABLES.....................................................................................................................10 LISTE DES ABREVIATIONS......................................................................................................11 PREAMBULE ET OBJECTIF DU TRAVAIL DE THESE..........................................................14 INTRODUCTION………………………………………………………………………………16 I. Définition……………………………………………................................................................16 II. Classification de la DI en fonction du QI…………………..................................................16 III. Classification de la DI en fonction de la clinique................................................................17 IV. Bases génétiques de la déficience intellectuelle..................................................………..…17 1. DI due aux anomalies chromosomiques….................................................................................18 1.1. DI due aux anomalies du nombre de chromosomes (aneuploïdies)........................................18 1.2. DI due aux anomalies de la structure des chromosomes (aneusomies segmentaires).............19 2. Déficience intellectuelle monogénique.......................................................................................24 2.1. Déficience intellectuelle liée à l'X...........................................................................................24 2.2. Déficience intellectuelle autosomique.....................................................................................25 V. Fonctions des gènes de la déficience intellectuelle…………………………………………26 1. Gènes impliqués dans la mise en circulation des vésicules pré synaptiques..............................28 2. Gènes impliqués dans l’organisation du compartiment postsynaptique.....................................28 3. Gènes impliqués dans la dynamique du cytosquelette...............................................................29 4. Gènes impliqués dans la cascade de signalisation intracellulaire...............................................30 5. Gènes impliqués dans la régulation épigénétique de la transcription.........................................30 VI. Continuum étiologique entre DI et autres phénotypes neurodéveloppementaux………31 VII. Déficience intellectuelle : quel mode d’hérédité ?..............................................................32 VIII. Mécanismes des réarrangements génomiques dans les maladies génomiques………..33 1. Recombinaison Homologue Non Allélique (NAHR) ................................................................33 2. Ligature d'extrémités d'ADN non homologues (Non Homologous End Joining ou NHEJ).............................................................................................................................................35 3. Fork Stalling and Template Switching (FoSTeS).......................................................................35 - 3 - MATERIEL ET METHODES…………………………………………………………..……..37 I. Recrutement des patients.............................................................................................................37 II.Méthodes.....................................................................................................................................37 1. Prélèvements des échantillons et extraction d’ADN…………………………..........................37 2. Analyse chromosomique sur microréseau d’ADN………………………….............................38 2.1. Contrôle de la qualité d’ADN………………………………………………..........................38 2.2. Digestion d’ADN par l’enzyme de restriction…………………………….............................39 2.3. Marquage des produits digérés……………………………………………............................40 2.4. Purifications des produits marqués………………………………………..............................40 2.5. Hybridation des produits purifiés………………………………………................................41 2.6. Lavage des lames………………………………………………………….............................41 2.7. Analyse des données………………………………………………………............................41 2.8. Différents types d’ACM utilisés…………………………......................................................43 3. PCR quantitative………………………………………………………………….....................44 3.1. Design des amorces………………………………………………………….........................45 3.2. Tester l’efficacité des amorces………………………………………………........................45 3.3. Analyse des résultats par la méthode 2-∆∆Ct………………………………….........................48 3.4. Amorces spécifiques des gènes de DI pour la qPCR…...........................................................49 4. Séquençage
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