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Corrélations Génotype/Phénotype Dans La Maladie De Charcot-Marie-Tooth L’Exemple Des Mutations Du Gène INF2

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Corrélations Génotype/Phénotype Dans La Maladie De Charcot-Marie-Tooth L’Exemple Des Mutations Du Gène INF2 UNIVERSITE DE LIMOGES ECOLE DOCTORALE BIOSANTE FACULTE DE MEDECINE Laboratoire : Maintenance myélinique et neuropathies périphériques (EA 6309) Thèse N° [-----] Thèse pour obtenir le grade de DOCTEUR DE L’UNIVERSITÉ DE LIMOGES Neurosciences présentée et soutenue par Stéphane MATHIS le 04 Décembre 2014 Corrélations génotype/phénotype dans la maladie de Charcot-Marie-Tooth L’exemple des mutations du gène INF2 Thèse dirigée par Benoît FUNALOT JURY : Rapporteurs M.TRICAUD Nicolas Chargé de recherche INSERM (HDR) à l’Université de Montpellier M.GOIZET Cyril Professeur à l’Université de Bordeaux Examinateurs M. STURTZ Franck Professeur à l’Université de Limoges M. FUNALOT Benoît Professeur à l’Université de Limoges M. NEAU Jean­Philippe Professeur à l’Université de Poitiers UNIVERSITE DE LIMOGES ECOLE DOCTORALE BIOSANTE FACULTE DE MEDECINE Laboratoire : Maintenance myélinique et neuropathies périphériques (EA 6309) Thèse N° [-----] Thèse pour obtenir le grade de DOCTEUR DE L’UNIVERSITÉ DE LIMOGES Neurosciences présentée et soutenue par Stéphane MATHIS le 04 Décembre 2014 Corrélations génotype/phénotype dans la maladie de Charcot-Marie-Tooth L’exemple des mutations du gène INF2 Thèse dirigée par Benoît FUNALOT JURY : Rapporteurs M.TRICAUD Nicolas Chargé de recherche INSERM (HDR) à l’Université de Montpellier M.GOIZET Cyril Professeur à l’Université de Bordeaux Examinateurs M. STURTZ Franck Professeur à l’Université de Limoges M. FUNALOT Benoît Professeur à l’Université de Limoges M. NEAU Jean-Philippe Professeur à l’Université de Poitiers à mes parents Remerciements Les études réalisées pour ce Mémoire se sont déroulées au sein du Laboratoire de recherche « Maintenance myélinique et neuropathies périphériques (EA 6309) » du CHU de Limoges, sous la direction de Monsieur le Professeur Benoît FUNALOT. Je le remercie vivement pour la confiance qu’il m’a accordée et pour m’avoir guidé dans ce travail. Que Monsieur Nicolas TRICAUD, chargé de recherche INSERM à l’Université de Montpellier (Institut des Neurosciences de Montpellier), et Monsieur Cyril GOIZET, Professeur à l’Université de Bordeaux (UFR des Sciences Médicales Bordeaux Segalen), trouvent ici toute l’expression de ma reconnaissance pour avoir accepté d’être rapporteurs de ces travaux, ainsi que pour leur participation à ce jury. Je remercie Monsieur le Professeur Jean-Michel VALLAT, Professeur à l’Université de Limoges, pour son accueil chaleureux au sein de son laboratoire de Neuropathologie et au sein du service de Neurologie du CHU de Limoges. Je le remercie également pour m’avoir permis d’utiliser des reproductions photographiques d’analyses histo-pathologiques effectuées au sein de son laboratoire. Je remercie Monsieur le Professeur NEAU, Professeur à l’Université de Poitiers (chef du service de Neurologie du CHU de Poitiers), pour m’avoir soutenu dans mes recherches. Je le remercie également pour avoir accepté d’être co-directeur de ces travaux et membre de ce jury. Je remercie Monsieur Franck STURTZ, Professeur à l’Université de Limoges (Chef du Service de Génétique du CHU de Limoges), pour l’intérêt qu’il a porté à ces travaux en acceptant de participer à ce jury. Je remercie Monsieur Roger GIL, Professeur à l’Université de Poitiers (ancien chef de service de Neurologie du CHU de Poitiers, ancien doyen de la Faculté de Médecine et de Pharmacie de Poitiers), pour m’avoir guidé dans ma formation de neurologue et m’avoir soutenu durant toutes ces années. Que Madame Laurence RICHARD et les techniciennes du laboratoire de Neuropathologie du CHU de Limoges soient remerciées pour leur soutien et leur aide technique précieuse. Je souhaite remercier mes collègues neurologues du CHU de Poitiers (Monsieur le Docteur Jonathan CIRON, Monsieur le Docteur Foucaud DUBOISGUEHENEUC, Madame le Docteur Isabelle BENATRU, Monsieur le Docteur Matthias LAMY et Monsieur le Docteur Adrien JULIAN) et du CHU de Limoges (Monsieur le Professeur Laurent MAGY et Madame le Docteur Karima GHORAB) pour la confiance qu’ils m’accordent et le soutien qu’ils m’apportent. Je remercie enfin tous les thésards que j’ai pu côtoyer durant ces trois années passées au Laboratoire. Sommaire Introduction .................................................................................................................................1 Le système nerveux périphérique ...............................................................................................3 Généralités ..............................................................................................................................3 Origine embryologique ...........................................................................................................5 Le nerf périphérique ....................................................................................................................8 Structure générale du nerf périphérique ..................................................................................8 Vascularisation du nerf périphérique ....................................................................................19 Axone et cytosquelette ..........................................................................................................20 Polarisation des cellules du système nerveux périphérique ..................................................24 Rôle des mitochondires au sein des nerfs périphériques ......................................................36 La cellule de Schwann ..........................................................................................................41 Définition des cellules gliales ...........................................................................................41 Origine et développement des cellules de Schwann .........................................................43 Le processus de gliogenèse ...............................................................................................45 Le processus de myélinisation ..........................................................................................46 Intéractions des cellules de Schwann avec la matrice extra-cellulaire .............................49 Rôle des GTPases .............................................................................................................53 Rôle des cellules de Schwann dans le processus inflammatoire des nerfs périphériques 57 Processus de dégénération/régénération du système nerveux périphérique .........................59 Les neuropathies périphériques .................................................................................................66 Définition clinique ................................................................................................................66 Moyens d’exploration habituels des neuropathies périphériques .........................................73 Biologie .............................................................................................................................73 Electrophysiologie ............................................................................................................75 Radiologie .........................................................................................................................90 Histopathologie .................................................................................................................93 La génétique ............................................................................................................................108 Généralités ......................................................................................................................108 L’ADN ............................................................................................................................108 L’ARN ............................................................................................................................110 Chromosomes : aspects normaux et pathologiques ........................................................111 Génes : aspects normaux et pathologiques .....................................................................115 Principales techniques de Génétique moléculaire ...........................................................117 La maladie de Charcot-Marie-Tooth ......................................................................................121 Généralités ..............................................................................................................................123 Données historiques ................................................................................................................128 Maladie de Charcot-Marie-Tooth de type 1 (CMT1) .............................................................130 CMT1A ...............................................................................................................................130 CMT1B ...............................................................................................................................135 CMT1C ...............................................................................................................................137 CMT1D ...............................................................................................................................138 CMT1E ...............................................................................................................................140 CMT1F ................................................................................................................................141
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