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Genetic Investigations of Sporadic Inclusion Body Myositis and Myopathies with Structural Abnormalities and Protein Aggregates in Muscle

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Genetic Investigations of Sporadic Inclusion Body Myositis and Myopathies with Structural Abnormalities and Protein Aggregates in Muscle Qiang Gang MRC Centre for Neuromuscular Diseases and UCL Institute of Neurology Supervised by Professor Henry Houlden, Dr Conceição Bettencourt and Professor Michael Hanna Thesis submitted for the degree of Doctor of Philosophy University College London 2016 1 Declaration I, Qiang Gang, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Signature………………………………………………………… Date……………………………………………………………... 2 Abstract The application of whole-exome sequencing (WES) has not only dramatically accelerated the discovery of pathogenic genes of Mendelian diseases, but has also shown promising findings in complex diseases. This thesis focuses on exploring genetic risk factors for a large series of sporadic inclusion body myositis (sIBM) cases, and identifying disease-causing genes for several groups of patients with abnormal structure and/or protein aggregates in muscle. Both conventional and advanced techniques were applied. Based on the International IBM Genetics Consortium (IIBMGC), the largest sIBM cohort of blood and muscle tissue for DNA analysis was collected as the initial part of this thesis. Candidate gene studies were carried out and revealed a disease modifying effect of an intronic polymorphism in TOMM40, enhanced by the APOE ε3/ε3 genotype. Rare variants in SQSTM1 and VCP genes were identified in seven of 181 patients, indicating a mutational overlap with neurodegenerative diseases. Subsequently, a first whole-exome association study was performed on 181 sIBM patients and 510 controls. This reported statistical significance of several common variants located on chromosome 6p21, a region encompassing genes related to inflammation/infection. WES was performed on a group of 35 cases with tubular aggregates/cylindrical spirals, and detected rare variants in known/candidate genes. Disease-causing genes were identified in four families with protein aggregates in muscle also by WES. In one family identified with a novel homozygous deletion in SBF1 with a rare autosomal-recessive neuromuscular condition, functional analysis was carried out indicating a loss-of-function mechanism underlying the pathogenesis of the disease. The collection of a large series of sIBM patients through the IIBMGC has been shown here to reveal important genetic findings and will be a valuable resource for the future. WES proved to be important in sIBM and also to be an efficient method to investigate the genetics basis of rare complex muscle disorders. 3 Acknowledgements First of all, I would like to thank my supervisors Professor Henry Houlden, Dr Conceição Bettencourt and Professor Michael Hanna for giving me the opportunity to work on this thesis. I express my deepest gratitude for their support, encouragement, scientific guidance and inspiration throughout the last four years. I specially thank Dr Pedro Machado for his coordination with sIBM study collaborators and his clinical knowledge and guidance when I needed it. I would like to thank Dr Alan Pittman for his guidance in bioinformatics; and also to thank Professor Janice Holton for her help with biopsy images. This PhD would also have not been possible without the support, help and guidance from all the members within the Department of Molecular Neuroscience, MRC Centre for Neuromuscular Diseases, and Neurogenetics Lab, in particular Debbie, Mark, Chris, Hallgeir, Estelle, David L, Lucia, Sarah W, Niccolo, Stephanie, Josh, Steven, Jack, James, Ese, Iwona, Enrico, Zuzanna, Renata, and Karen. Special thanks also go to Alice, Ellen, Monika, Siobhan, and Amelie, for their advice and friendship - sharing an office with them has been a pleasure; my gratefulness in particular to Alice for her time to comment on this thesis. I am also hugely grateful to my family, in particular to my parents for their never- ending love, support, and belief in me to allow me to pursue my dreams; also to my aunt and uncle, Yi Gang and Zhong-Yi Zhang, for their excellent care and for providing me with a comfortable home since I first arrived in London six years ago. I would also like to thank my cousin, Xiao-Yin, and her husband, Matthew, for their encouragement and also for taking the time to read through this thesis. I also thank my dear friends from UCL, Ya Hu, Bao-Luen Chang, Li-Xun Liu, Jin Si, Xing-Wei Zhao, Xi Ji, and many others with whom I have shared the ups and downs of our PhD life, and made it an unforgettable period of my life. I would like to extend my thanks to the UCL Impact Studentship and Chinese Scholarship Council, who provided financial support during my PhD. Lastly, thanks 4 to all the collaborators, patients and their families who have taken part in the studies in this thesis. 5 Table of Contents Declaration.................................................................................................................. 2 Abstract………………………………………………………………………………3 Acknowledgements ..................................................................................................... 4 Table of Contents ....................................................................................................... 6 List of Figures ........................................................................................................... 12 List of Tables ............................................................................................................. 15 List of Abbreviations ................................................................................................ 18 List of Publications Arising from This Thesis ....................................................... 25 Chapter 1 Introduction ........................................................................................ 28 1.1 Phenotypic Spectrum of Myopathies and Myositis ..................................... 28 1.1.1 Skeletal Muscle .................................................................................... 28 1.1.2 Classification of Myopathies ................................................................ 30 1.1.3 Idiopathic Inflammatory Myopathies ................................................... 32 1.2 Sporadic Inclusion Body Myositis (sIBM) .................................................. 34 1.2.1 Prevalence of sIBM .............................................................................. 34 1.2.2 Clinical and Pathological Phenotypes of sIBM .................................... 35 1.2.3 The Diagnosis of sIBM ........................................................................ 38 1.2.4 Possible Pathogenesis of sIBM ............................................................ 40 1.2.5 Genetic Contributions to sIBM ............................................................ 46 1.2.6 Animal Models of sIBM ...................................................................... 54 1.3 Myopathies with Specific/Rare Structure Abnormalities and with Protein Aggregates .............................................................................................................. 55 1.3.1 Myopathies with Tubular Aggregates and Cylindrical Spirals ............ 57 1.3.2 Myopathies with Cytoplasmic Bodies.................................................. 68 1.3.3 Centronuclear Myopathies and Myotubular Myopathy ....................... 68 6 1.4 Application of Genetic Techniques in Mutation Detection and Gene Discovery ............................................................................................................... 70 1.4.1 Traditional Genetic Techniques ........................................................... 71 1.4.2 Next-Generation Sequencing ............................................................... 72 1.5 Thesis Aims ................................................................................................. 78 Chapter 2 Materials and Methods ...................................................................... 79 2.1 Patients Collection and Ethical Approval ................................................... 79 2.1.1 IBM Patients ........................................................................................ 79 2.1.2 Other Patients ....................................................................................... 80 2.1.3 Samples Collection .............................................................................. 81 2.1.4 Ethical Approval .................................................................................. 81 2.2 Genetic Studies ............................................................................................ 82 2.2.1 DNA Extraction from Blood and Muscle Tissue ................................. 82 2.2.2 DNA Concentration and Purity ............................................................ 82 2.2.3 Polymerase Chain Reaction (PCR) and Sanger Sequencing ............... 82 2.2.4 Mutation Nomenclature ....................................................................... 85 2.2.5 Restriction Endonuclease Analysis ...................................................... 85 2.2.6 MAPT Genotyping ............................................................................... 87 2.2.7 PRNP Genotyping at Codon 129 ......................................................... 87 2.2.8 Fragment Analysis ............................................................................... 88 2.2.9 Long PCR for mtDNA
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