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Thesis, I Have Studied Rare Monogenic Novel Neurodevelopmental Disorders Associated with ID

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Thesis, I Have Studied Rare Monogenic Novel Neurodevelopmental Disorders Associated with ID APPLYING ANIMAL MODELLING TO UNDERSTAND RARE NOVEL NEURODEVELOPMENTAL DISORDERS ASSOCIATED WITH INTELLECTUAL DISABILITY Maria Levitin St. John’s College University of Cambridge Wellcome Sanger Institute This dissertation is submitted for the degree of Doctor of Philosophy. September 2017 Applying animal modelling to understand rare novel neurodevelopmental disorders associated with intellectual disability Maria Levitin Intellectual disability (ID) is categorised by a significant reduction in cognitive function and adaptive abilities that begin in childhood. ID is part of a heterogeneous group of neurodevelopmental conditions associated with impairment in developmental domains and a cause of particularly adverse socioeconomic impact worldwide. There have been many recent advances in identifying causative genetic mutations in previously unexplained ID cases. With these advances comes an increasing demand for understanding mechanisms underpinning these pathogenic pathways. In this PhD thesis, I have studied rare monogenic novel neurodevelopmental disorders associated with ID. The objective of the thesis was to model a subset of mutations associated with novel neurodevelopmental disorders in mice to demonstrate a causal link between mutation and phenotype and to further understand the mechanisms by which these mutations result in human neurodevelopmental disorders. In order to achieve this, I adopted a multi-phase approach. Firstly, I designed a phenotyping platform, by combining behavioural and cognitive tests with morphometric brain analysis and genome-wide transcriptional analysis. I then used this approach to study KPTN-related syndrome, a novel developmental disorder that to date has not been characterised in mice, successfully recapitulating the main phenotypes described in the patients. Moreover, I gained further insight into the underlying pathogenic mechanisms associated with the disorder, opening the possibility of a therapy that could treat some aspects of cognitive and morphological impairments identified in the patients with KPTN-related syndrome. Lastly, I determined whether such an approach could be scaled-up to study multiple novel neurodevelopmental disorders, each with a mutation associated with a haploinsufficient novel neurodevelopmental disorder. I identified specific phenotypes for each of the four mouse lines under investigation, providing a platform for comparison between several developmental disorders. These refinements contributed to a larger five-year project starting at the Sanger Institute, aimed at characterising a wider diversity of human neurodevelopmental disorders. DECLARATION This dissertation is the result of my own work and includes nothing which is the outcome of work done in collaboration except as declared in the contributions section within each chapter and/or specified in the text. It is not being concurrently submitted for a degree or diploma or other qualification at the University of Cambridge or any other University or similar institution. I further state that no substantial part of my dissertation has already been submitted, or, is being concurrently submitted for any such degree, diploma or other qualification at the University of Cambridge or any other University of similar institution. It does not exceed the prescribed word limit for the Faculty of Biology. Maria Levitin September 2017 ACKNOWLEDGEMENTS The PhD is a transformative journey with many ups and downs. Words cannot do justice to how thankful I am to all the incredible people who were a part of this journey and made it a memorable positive experience. First of all, I want to thank my supervisor, Darren Logan. Darren guided and supported me from the very first day I decided to try real science as an Undergraduate Placement student in his lab, to the last days of thesis writing when he was just a phone call and train journey away despite the physical distance, and beyond the PhD submission. I am grateful for having such a wonderful role model – both on a scientific and a human being level. I want to thank Matt Hurles for adopting me to his team and giving me all the resources I needed for the smooth running of my PhD project. I want to also say thank you to all the members of the Hurles group for welcoming me and being there whenever I needed anything. I want to give a big thank you to Sebastian Gerety for taking me under his wing when all the changes happened, countless hours of productive discussions, always encouraging me to do my very best and, leading by example, striving to achieve the highest quality of science possible. It has been very inspiring to have a mentor who is so passionate about what he does. I would also like to thank my behavioural guru Gabi Gurria for all her mentorship and help over the years. Gabi not only taught me so much about behavioural neuroscience, but she is also one of the nicest people I know; working with her has been truly a pleasure. I want to thank all the other members of the team 156 – Elizabeth Wynn, Luis Saraiva, Ximena Ibarra-Soria, Cristina Dias, Laura Huckins, Sophia Liang – for all the help and insightful discussions they have provided and all the fun we had in and out of the lab. I also want to thank the cognition sub-team, including Mark Sanderson and Holly Ironfield, for a huge amount of hands-on help with behavioural experiments (Mark) and molecular work (Holly and Elizabeth). My PhD experience would not be the same without the fantastic friends I made in Cambridge, St. John’s College, and at the Sanger Institute. The Sanger PhD program was an incredible support system throughout the whole PhD experience, and for this, I am thankful to the Graduate Office (Carl Anderson, Annabel Smith, and Christina Hedberg-Delouka) and the PhD community. Shout out goes to PhD13, my PhD year group, and the other wonderful Sanger PhDs. From the daily breakfast, lunches, and courses together, to long gossip sessions and crazy night outs on the choo-choo train – we have been through a lot with these humans and I am very grateful for such a lovely year group. I want to put a particular emphasis on two groups of PhD friends who also became my elected family. You all know how much I love you so I will try (and fail) to keep it brief. Firstly my Sanger family – Velislava Petrova, Fernando Riveros Mckay Aguilera, Liliana Antunes, Dimitris Garyfallos, Gianmarco Raddi, Christian Owusu, and Alice Mann. Veli has been my EEBmate from the first (unconventional) day we met, she is the person who knows me inside out, and without her, my PhD would have been a completely different experience, so would have my life in general. Fernando is not only one of my best friends and a person I can rely on at any point no matter the circumstance, but he was also my go-to RNA sequencing analysis expert and helped greatly towards the end of my PhD with all the RNA sequencing data that was flooding in. I will be forever in debt to Liliana, for being an incredible friend who I could always rely on, the mode of transport for all weekend trips to the lab (with picnics), a complete life-saver during my thesis submission, and the responsible yet flowery presence in our group. The two BBs, Dimitri and Gianmarco, became my besties pretty much straight away and each in their own way became an important component of my PhD journey and without whom I could not imagine Sanger and Cambridge in general. Christian, my horror movie buddy, has always provided me with fascinating discussions and lots of positivity (even though he tried to mask it with grumpiness). Alice and I shared a love for organising and chats over hot beverages and made a great team throughout the PhD as a consequence. Secondly, I want to say a big thank you to my St. John’s ladies – Rishika Kundra and Molly Krasnodebska. These women were one of the very first people I met as I moved to Cambridge and they made me feel like I was home immediately. We have gone through our PhD journeys hand in hand and having them in my life, and for a long time as my housemates, has truly made a big difference to my time in Cambridge. I also want to thank all my friends out of Cambridge, near and far, who had to deal with me in PhD mode and were nevertheless always very understanding and supportive. Yes, Trajche you may have the spotlight too buddy, because of your impressive persistence with which you demanded to be mentioned in my thesis. I also want to thank Molly Cranston, for looking over my thesis with unbiased and trained eyes, which was very useful. I want to give a big and probably not enough times articulated thank you to one very loving and very patient man, Petros Sideris, who was there in the front row seat for all that PhD threw my way and was able to keep me sane throughout the whole process. He also survived the final month of living with a thesis-writing zombie and helped a tremendous amount in the most panic-heavy moments. And finally, I want to thank the people who are the reason I got to do a PhD in the first place and have made me who I am today. More than words can ever portray – I am forever grateful for having such amazing parents who have always inspired and encouraged me to follow my dreams and believe in myself, and gave me the necessary skills and resources to make this a reality. I also want to thank my grandparents, who have since a young age doomed me to become a scientist by evoking a sense of curiosity for the unknown and the unexplored. Abbreviations and acronyms 4E-BPs eIF4E-binding proteins ADHD Attention deficit hyperactivity disorder ASD
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