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DISRUPTION of RAS-MAPK SIGNALLING in HUMAN NEUROCUTANEOUS DISORDERS

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DISRUPTION of RAS-MAPK SIGNALLING in HUMAN NEUROCUTANEOUS DISORDERS DISRUPTION of RAS-MAPK SIGNALLING in HUMAN NEUROCUTANEOUS DISORDERS (Thesis format: Integrated Article) by Laura Marie McDonell Graduate Program in Biochemistry with specialization in Human and Molecular Genetics A thesis submitted in partial fulfillment of the requirements for the degree of Doctor in Philosophy The Faculty of Medicine Graduate and Postdoctoral Studies The University of Ottawa, Ottawa, Ontario, Canada © Laura Marie McDonell, Ottawa, Canada, 2018 Abstract Ras-MAPK signalling regulates key cellular processes such as proliferation, differentiation and survival. Unsurprisingly, mutations in RAS genes are now recognized as potent oncogenic drivers. However, disruption of this pathway during development is associated with a family of disorders termed the Rasopathies. Shared clinical features include cutaneous, neurological and cardiac anomalies. At the outset of this study, the genetic etiology of three neurocutaneous disorders, microcephaly-capillary malformation syndrome (MIC-CAP), encephalocraniocutaneous lipomatosis (ECCL) and PHACE (Posterior fossa malformations, facial Hemangiomas, cerebral Arterial anomalies, Cardiovascular defects and Eye abnormalities) syndrome had not yet been established. This thesis identifies mutations in STAM-binding protein (STAMBP) in a cohort of individuals with MIC-CAP syndrome using whole-exome sequencing (WES). This gene encodes a deubiquitinating isopeptidase that regulates cell surface receptor-mediated endocytosis and sorting. Cell lines of individuals with MIC-CAP show reduced STAMBP expression, associated with accumulation of ubiquitinated protein aggregates, increased apoptosis and constitutive activation of the Ras-MAPK and PI3K-AKT pathways. WES also enabled the identification of post-zygotic mutations within the tyrosine kinase domain of fibroblast growth factor receptor 1 (FGFR1) in individuals with ECCL. Fibroblasts from affected individuals showed increased phosphorylation of the FGFRs consistent with receptor activation as well as insensitive signal transduction through the Ras-MAPK pathway. Neurocutaneous syndromes can feature striking vascular lesions such as the cerebral vasculopathy and large segmented facials hemangiomas seen in PHACE syndrome. The asymmetric and patchy vascular malformations coupled with a sporadic incidence and absence of familial recurrence suggested that PHACE might be caused by post-zygotic mutations. Interrogation of a discordant sib-pair using copy number analysis and WES did not identify ii causative mutations indicating the need for a comprehensive and targeted –omic approach to elucidate the molecular mechanism of this syndrome. Taken together, these findings expand the spectrum of the Rasopathies while providing novel pathomechanistic insights into the regulation of cellular proliferation and survival during development. iii Acknowledgements This thesis would not have been possible without the participation of the many patients and families whose stories contribute to the work presented herein. I would like to thank all the clinicians, scientists, laboratory technicians, genetic counsellors and other team members who have, and continue to, support the CareforRare initiative. I am forever grateful to Dr. Kym Boycott whose leadership, infallible work ethic and unwavering dedication to her field has been both inspiration and motivation. You have provided mentorship, academic challenges and innumerable learning opportunities and have contributed to my growth as a clinician-scientist trainee. I will proudly carry forward the lessons you have taught me. Thank you. I would like to express my deepest gratitude to Dr. Dennis Bulman, my lab father, who first encouraged me to apply to the MD/PhD program. You provided me with perspective, guidance and steadfast encouragement. Your incredible knowledge of molecular genetics was a wonderful asset throughout my graduate studies. I am grateful to all our collaborators whose patients, expertise and labour colour these pages. In particular, I would like to thank Dr. Mark O’Driscoll and his lab, whose cell biology work provided invaluable depth to our stories and who was willing to take me in. I would like to thank every single lab member, past and present, whose names and stories could fill many pages. Thank you for supporting me all of these years. Each of you holds a special place in my heart and I will not forget all of the laughs, challenges, success and popcorn we have shared. iv And finally, thank you to my family, friends and loved one for showering me with their unconditional love and endless support. It would not have been possible without you. v Table of Content Abstract ............................................................................................................................................ ii Acknowledgements .......................................................................................................................... iv Table of Content .............................................................................................................................. vi Abbreviations ................................................................................................................................... ix List of Tables .................................................................................................................................. xv List of Figures ................................................................................................................................ xvi List of Appendices ....................................................................................................................... xvii Chapter 1 ........................................................................................................................................... 1 1. General Introduction .............................................................................................................................. 1 1.1 Ras-MAPK signalling ...................................................................................................................... 1 1.1.1 Ras family ................................................................................................................................................ 2 1.1.2 Signal transduction in the Ras pathway ................................................................................................... 3 1.1.3 Downstream effectors of Ras-MAPK signalling ..................................................................................... 3 1.1.4 Ras-MAPK signalling in oncogenesis ..................................................................................................... 7 1.1.5 Ras-MAPK signalling in development and post-natal life ...................................................................... 8 1.2 Neurocutaneous disorders .............................................................................................................. 11 1.2.1 Cutaneous manifestations ...................................................................................................................... 11 1.2.2 Neurological involvement ...................................................................................................................... 12 1.2.3 Contributing pathways ........................................................................................................................... 14 1.2.4 Mosaic neurocutaneous disorders .......................................................................................................... 15 1.3 High-throughput sequencing ......................................................................................................... 17 1.3.1 Clinical application of whole-exome sequencing .................................................................................. 17 1.4 Thesis Overview ............................................................................................................................ 19 1.4.1 Rationale and Hypothesis ....................................................................................................................... 19 1.4.2 Chapter 2: Microcephaly-capillary malformation syndrome ................................................................. 19 1.4.3 Chapter 3: Encephalocraniocutaneous lipomatosis ................................................................................ 20 1.4.3.1 Encephalocraniocutaneous lipomatosis and FGFR1 ...................................................................... 20 1.4.3.2 Encephalocraniocutaneous lipomatosis and KRAS ........................................................................ 21 1.4.4 Chapter 4: PHACE syndrome ................................................................................................................ 21 1.5 References ...................................................................................................................................... 22 vi Chapter 2: Microcephaly-capillary malformation syndrome .................................................... 26 2.1 Preface ................................................................................................................................................ 26 2.2 Statement of permission for use of copyrighted material .................................................................. 26 2.3 Contributions .....................................................................................................................................
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