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Identification and Characterisation of the Underlying Defects in Patients with Inherited Platelet Bleeding Disorders

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Identification and Characterisation of the Underlying Defects in Patients with Inherited Platelet Bleeding Disorders Identification and Characterisation of the Underlying Defects in Patients with Inherited Platelet Bleeding Disorders By: Maryam Ahmed Aldossary A thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy The University of Sheffield Faculty of Medicine, Dentistry and Health Department of Infection, Immunity & Cardiovascular Disease Submission Date January 2019 Abstract The underlying genetic defects remain unknown in about 50% of inherited platelet bleeding disorders (IPDs). This study investigated the use of whole exome sequencing (WES) to identify candidate gene defects in 34 index cases enrolled in the UK Genotyping and Phenotyping of Platelets study with a history of bleeding, whose platelets demonstrated defects in agonist-induced dense granule secretion or Gi- signalling. WES analysis identified a median of 98 candidate disease-causing variants per index case highlighting the complexity of IPDs. Sixteen variants were in genes that had previously been associated with IPDs, two of which were selected for further characterisation. Two novel FLI1 alterations, predicting p.Arg340Cys/His substitutions in the DNA binding domain of FLI1 were shown to reduce transcriptional activity and nuclear accumulation of FLI1, suggesting that these variants interfere with the regulation of essential megakaryocyte genes by FLI1 and may explain the bleeding tendency in affected patients. Expression of a novel truncated p.Arg430* variant of ETV6 revealed it to be stably expressed, possessing normal repressor activity in HEK 293T cells and a slight reduction in repressor activity in megakaryocytic cells. Further studies are required to confirm the pathogenicity of this variant. To identify novel genes involved in platelet granule biogenesis and secretion, gene expression was examined in megakaryocytic cells before and after knockdown of FLI1, defects in which are associated with platelet granule abnormalities. Comparison of the gene expression data with that from platelets from patients with FLI1 defects and with the results of WES analysis in patients with secretion defects highlighted several genes of interest, including C18orf32, IGFBP2, PLCG2, SCFD2, SLC24A3, ST8SIA6 and ZBTB45 which, between them, harboured ten candidate causative variants among the patients with defects in platelet secretion. Further work is warranted to explore the contribution of these genes to platelet secretory pathways. ii Acknowledgements Firstly, I would like to express my genuine appreciation to my supervisor Prof Martina Daly for her help. Her guidance, support, motivation, enthusiasm and patience helped me at each step during the last four years at both the academic and non-academic level. I could not have imagined having a better advisor and mentor for my PhD study. Also, I would like to thank Prof Michael Makris for his insightful comments and encouragement and Dr Vincenzo Leo for his patience and valuable support, especially during the first year. With a special mention, I also would like to thank Dr Simon Webster for his help, suggestions, and insight, which drove me to think deeply during our discussions in the lab. Also, I would like to thank all the members of the Haemostasis group, including Dr Dan Hampshire, Prof Anne Goodeve and Ian Peake for their comments, questions and support, and for all the laughs and fun that we have had during the last four years. It was fantastic to have had the opportunity to be a member of the Sheffield Haemostasis group. I would also like to express my appreciation for all those from outside the University of Sheffield who helped in various aspects during my PhD: The UK-GAPP study coordinator Dr Neil V. Morgan from the University of Birmingham, UK, and all members of the UK-GAPP study group; Our collaborators Dr Courtney D. Thornburg and Diane Masser-Frye from Rady Children’s Hospital, San Diego, USA, who identified and provided details of the second FLI1 patient; Dr Michael Simpson of King’s College London, UK, who carried out the whole exome sequencing. Additionally, Dr Maria Trojanowska from Boston University, USA, for providing us with the FLI1 plasmid and Dr Leila Noetzli from the University of Colorado Anschutz Medical Campus, USA, and Michael Y. Zhang from the University of Washington, USA, for providing the ETV6 plasmids. Equally, I am grateful for all the support that was provided from within the University of Sheffield. I would like to thank all the core facilities for their support, especially Sheffield Microarray and Next Generation Sequencing Core Facility in the Sheffield Institute for Translational Neuroscience (SITRAN), the Medical School Flow Cytometry Core Facility, Wolfson Light Microscopy Facility, and the Core Genomic Facility. Additionally, special thanks to all the technical staff, the PGR team, the medical IT team, the administrative staff and the members of the medical school. Also, I would like to thank my colleagues in our student office and all other students for their chats, smiles, help and a few µl of reagents. Additionally, I would like to acknowledge my sponsors, the “Imam Abdurrahman bin Faisal University” and the British Heart Foundation, who initially funded the UK-GAPP study. Also, I would like to thank the Saudi Arabian Cultural Bureau and the Embassy of Saudi Arabia in the UK for their efforts. I am grateful to Dr Layla Bashawri for introducing me to research, to Dr Sarah Alshamari for making this possible and to Dr Faisal Alzahrani for his encouragement in taking this step. Last but not least, I would like to express my great love, debt and appreciation for my mother Hussah and my father Ahmed, who kept pushing me towards this point. Additionally, I would like to thank my sisters, brothers and aunts and all my family and friends who have supported me along the way and in my life in general. I should also not forget my husband and my two lovely daughters for being there for me. iii Dedication “This is dedicated … To my grandpa Abdul-Aziz. Although it has been three years since you left us, I still do not know how I will keep visiting that house and seeing your favourite place on that couch empty. I miss you being around, giving your blessing, and being a part of all the special moments in our lives. Of all the times, 9pm every day, the time that we expected you to return from your office, is one of the most difficult times, without hearing the noise of the garage door opening, seeing your car approaching through that large window in the living room, and listening to your short steps before you opened the door with a smile and carrying a bag of hot fresh bread. I really miss you a lot and everything that left with you. To my beloved mum Hussah, who keeps motivating me throughout my life. To my dear dad Ahmed, who keeps making me dream. Your big heart that gives unconditional love, your ultimate care, attention and support that include even all the minor details in my life, your strictness and passion about my education, you are one of a kind. I could not have any better parents and I wish to give my kids part of what you gave me. To you. Because I owe it all to you. Many Thanks” iv Table of Contents ABSTRACT ........................................................................................................ II ACKNOWLEDGEMENTS ................................................................................. III DEDICATION .................................................................................................... IV TABLE OF CONTENTS ..................................................................................... V LIST OF FIGURES ............................................................................................. X LIST OF TABLES ............................................................................................ XII APPENDICES ................................................................................................ XIV LIST OF SUPPLEMENTARY DATA ............................................................... XV LIST OF ABBREVIATIONS ........................................................................... XVI POSTER AND ORAL PRESENTATIONS ARISING FROM THIS WORK... XVIII 1 CHAPTER 1. INTRODUCTION ................................................................ 19 1.1 INTRODUCTION ............................................................................... 20 1.1.1 Megakaryopoiesis and platelet production ................................. 20 1.1.2 Platelet ultrastructure .................................................................. 22 1.1.3 The role of platelets in primary haemostasis .............................. 24 1.1.3.1 Initiation ................................................................................... 25 1.1.3.2 Secretion ................................................................................. 26 1.1.3.3 Extension................................................................................. 28 1.1.3.4 Consolidation / Aggregation .................................................... 29 1.1.3.5 Platelet Procoagulant Activity .................................................. 31 1.1.4 Inherited platelet bleeding disorders ........................................... 31 1.1.4.1 The molecular basis of inherited platelet disorders ................. 31 1.1.4.2 Diagnosis of inherited platelet function disorders .................... 33 1.2 THE AIMS OF THIS STUDY ............................................................. 36 2 CHAPTER 2. MATERIALS AND METHODS ..........................................
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