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Identification of Novel Genetic Causes of Monogenic Intellectual Disability Francesca Mattioli

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Identification of novel genetic causes of monogenic intellectual disability Francesca Mattioli To cite this version: Francesca Mattioli. Identification of novel genetic causes of monogenic intellectual disability. Neuro- biology. Université de Strasbourg, 2018. English. NNT : 2018STRAJ035. tel-01963143 HAL Id: tel-01963143 https://tel.archives-ouvertes.fr/tel-01963143 Submitted on 21 Dec 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. UNIVERSITÉ DE STRASBOURG ÉCOLE DOCTORALE DES SCIENCES DE LA VIE ET DE LA SANTE Institut de Génétique et Biologie Moléculaire et Cellulaire THÈSE présentée par : Francesca MATTIOLI soutenue le : 26 Juin 2018 pour obtenir le grade de : Docteur de l’université de Strasbourg Discipline/ Spécialité : Aspects Moléculaires et Cellulaires de la Biologie Identification of Novel Genetic Causes of Monogenic Intellectual Disability THÈSE co‐dirigée par : M MANDEL Jean-Louis Pr, Collège de France, IGBMC, Strasbourg Mme PITON Amélie MCU‐PH, Université de Strasbourg, IGBMC, Strasbourg RAPPORTEURS : Mme RENIERI Alessandra Pr, Università di Siena M REYMOND Alexandre Pr, Center for Integrative Genomics, Lausanne AUTRES MEMBRES DU JURY : M SERAPHIN Bertrand DR CNRS, IGBMC, Strasbourg Mme ZWEIER Christiane Pr, Institute of Human Genetics, Erlangen 1 ACKNOWLEDGMENTS I would like to thank Alessandra Renieri, Alexandre Reymond, Bertrand Seraphin and Christiane Zweier for accepting to be part of the jury, for evaluating my work and for having found time in your busy schedule to come and take part at my PhD defence. These (almost) four years have been really important to me, for my professional and personal growth. Of these, I would like to thank Jean‐Louis and Amélie for accepting me in their équipe and trusting me since the beginning. I’m really honored to be part of your team and you both guided me into becoming closer to the scientist I want to be. Amélie, I cannot thank you enough for your supervision: you patiently taught me everything and you have been always present for any problem. You have been really a model to me of super‐woman in science! Jean‐Louis, thank for you for your leading by example, your tremendous knowledge that is really inspiring… and for the alsatian gourmet advises! Thanks to all the people in the small Mandel’s lab, for the friendly environment: the current members, particularly Jérémie and Florent for the daily help, but also to the previous members, remarkably Angélique for being always willing to solve any problem (especially with the cells!), and for all the chocolate moments. Thanks to the X‐fra group, particularly Eric for his tips on the molecular and cloning techniques, and to the Chelly’s team for having welcomed us in the ICS. I would like to particularly thank Nathalie for the help with the libraries (but not only) and to Vicky, especially in the last period, for the microscope expertise. Thanks to the people of the TMN department for the constant sharing of protocols, reagents and ideas: it has been really of help for my work. Thanks to all the people in the facilities that really simplified the work: the cell‐culture, the molecular biology (grazie Paola per i plasmidi!) and especially to the people in the sequencing platform, for being always supportive and willing to help. A big thank to the bioinformaticians that were involved in the different projects. Thanks also to the funding agencies, particularly the Fondation Jérôme Lejeune. Then, as a PhD is not always about science, thanks to the friends that I found at the IGBMC. Thanks to the Obama’s girl: Dami, Lorraine and Samantha. Thanks for the support and all the laugh that we had. Now we are spread over three continents, but I really hope we are going to meet again soon. Thanks also to the koalas Arielle and Tiphaine for sharing our troubles and comfort each other. Thanks to the Italian community and its friends for understanding and sharing our culinary and loud‐speak problems. Ed infine, il mio core parla italiano (Cit). Sono stati quattro anni difficili, ma ho sempre avuto persone che mi hanno fatto sentire a casa e ricaricare le pile per affrontare al meglio tutti i problemi. Per questo vorrei ringraziare i colleghi‐amici “pavesini”, per condividere più o meno le stesse esperienze e rimanere comunque uniti, nonostante le distanze. Ed infine, vorrei ringraziare lo zoccolo duro ferrarese: Annina, Borin, Fede (si, anche tu sei ferrarese), Giammi, Laura, Porrig e Zolia. Nonostante gli anni e le distanze, ritornare al porto sicuro per me vuol dire anche rivedervi. Non potro mai ringraziare abbastanza Antonio per il totale su(o)pporto in questi anni. Sei stato il miglior compagno di dottorato che potessi avere. Sono contenta di avere condiviso questo percorso difficile con te ma non vedo l’ora di iniziare altre avventure insieme. Ultimi ma per niente ultimi, un ringraziamento alla mia famiglia, per il costante sostegno e per avermi fatto le spalle larghe attorno a quel famoso tavolo bianco in cucina. Tutto questo non sarebbe stato possibile senza di voi. 2 SUMMARY Résumé de la thèse .................................................................................................................................... 6 LIST OF TABLES ......................................................................................................................................... 13 LIST OF FIGURES ....................................................................................................................................... 14 LIST OF ABBREVIATIONS ........................................................................................................................ 17 INTRODUCTION ..................................................................................................................................... 18 1. DEFINITION OF INTELLECTUAL DISABILITY ........................................................................................ 19 2. COMORBIDITIES OF ID .......................................................................................................................... 20 3. ETIOLOGY OF ID .................................................................................................................................... 22 3.1 ENVIROMENTAL FACTORS ........................................................................................................... 23 3.2 GENETIC CAUSES ............................................................................................................................ 24 3.2.1 CHROMOSOMAL ABNORMALITIES ....................................................................................... 24 3.2.2 COPY NUMBER VARIATIONS (CNVs) ..................................................................................... 24 3.2.3 MONOGENIC FORMS OF ID .................................................................................................... 25 3.3 MORE COMPLEX FORMS OF ID ...................................................................................................... 31 4. GENETIC OVERLAP BETWEEN NEURODEVELOPMENTAL DISORDERS ................................................ 32 5. MOLECULAR PATHWAYS INVOLVED IN ID ........................................................................................... 35 5.1 METABOLIC DISORDERS .............................................................................................................. 35 5.2 SYNAPSE AND CYTOSKELETAL REGULATION AND ORGANIZATION .............................................. 35 5.3 GENE EXPRESSION REGULATION: TRANSCRIPTIONAL REGULATION ............................................ 37 5.3.1. DNA METHYLATION ............................................................................................................... 39 5.3.2 HISTONE MODIFIERS ............................................................................................................... 39 5.4 GENE EXPRESSION REGULATION: POST‐TRANSCRIPTIONAL REGULATION .................................. 41 5.4.1 mRNA MATURATION............................................................................................................... 42 5.4.2 mRNA EXPORT ......................................................................................................................... 45 5.4.3 mRNA LOCALIZATION .............................................................................................................. 45 5.4.4 TRANSLATION .......................................................................................................................... 46 5.4.5 mRNA DEGRADATION ........................................................................................................... 47 5.4.6 tRNAs ....................................................................................................................................... 51 5.4.7 RNA MODIFICATIONS ........................................................................................................... 52 6. NEXT‐GENERATION SEQUENCING APPLICATIONS IN ID .....................................................................
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