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Investigation of the Molecular Basis of Three New Disorders of Brain Growth and Development Identified Amongst the Amish

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Investigation of the molecular basis of three new disorders of brain growth and development identified amongst the Amish Dr Emma Louise Baple PhD Thesis 2014 Investigation of the molecular basis of three new disorders of brain growth and development identified amongst the Amish Submitted by Dr Emma Louise Baple to the University of Exeter as a thesis for the degree of Doctor of Philosophy in Medical Studies, September 2014. This thesis is available for Library use on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. I certify that all material in this thesis which is not my own work has been identified and that no material has previously been submitted and approved for the award of a degree by this or any other University. (Signature) ……………………………………………………………………………… 1 2 ACKNOWLEDGMENTS First and foremost I would like to thank the families who took part in these studies and the Amish community for their support of the wider Windows of Hope project. I am eternally grateful to my primary supervisor Professor Andrew Crosby, without whom I would never have had all the wonderful experiences this PhD brought me. I would also like to extend my thanks to Professor Michael Patton who has always supported and encouraged me in whatever scientific or clinical endeavours I have followed. Professor Nigel Brown, Professor Steve Jeffery and Dr Paris Ataliotis based at St George’s University of London provided invaluable support and advice throughout my PhD. Since arriving in Exeter, Dr Charles-Shaw Smith joined my supervisory team and I am hugely appreciative of his guidance and encouragement. None of the work in this thesis would have been possible without the other members of the Windows of Hope project team, Professor Harold Cross, Roselyn Coblentz, Karin Wagner and honorary member Ray Coblentz. I would like to thank all the members of the Crosby group for their help and support, but in particular Dr Barry Chioza, Dr Ajith Nair, Katy Barwick, Reza Maroofian and Gaurav Harlalka without whom this thesis would never have been completed. During the course of this PhD I was fortunate to collaborate with many other scientists and clinicians and I would like to thank them all for their contributions. I am particularly grateful to Dr Catherine Green who has helped and encouraged me immeasurably, never giving up on trying to identify the biochemist within me. I would also like to specifically mention Dr Andrew Jackson who supported the MRC clinical fellowship that funded a substantial proportion of this work and welcomed me into his lab. Dr Sahar Mansour was a source of great support and help when describing the clinical phenotypes 3 described in this thesis and analysis of neuroradiology would not have been possible without Dr Phil Rich. On a personal level I would like to thank my colleagues Dr Martina Muggenthaler and Dr Olivia Wenger for their friendship and constant helpful advice, my parents and brother who have always been there for me and my husband Peter Savage without whom none of this would have been possible. The work in this thesis was funded by Newlife foundation for disabled children and the Medical Research Council. 4 ABSTRACT Extremes of brain growth have frequently been associated with impaired neurodevelopment and cognition. A significant contribution to our understanding of the processes involved in brain development has been made by the study of single gene disorders which are rare in the general population, but occur with increased frequency in certain endogamous populations. This project stems from findings of a long-running clinical-genetic program, called ‘Windows of Hope’, based amongst the Amish. The project aims were to clinically characterise three new autosomal recessive disorders of brain growth and development, to define the genes and mutations responsible for each, and to investigate the function of the molecules identified. A final further objective of the project in keeping with the wider aims of the Windows of Hope study was to translate the findings of this research into direct clinical benefits to the families and community involved. A combination of clinical phenotyping, autozygosity and linkage mapping, and functional studies, were used to investigate each disorder, which enabled the identification of the novel disease genes in each case. Chapter three describes the identification of a hypomorphic mutation in PCNA responsible for a novel DNA repair disorder. Thus, although it was considered by many that mutations in PCNA would not be compatible with life due to its crucial role in genomic stability and cell division, this study disproves this notion and describes a molecular ‘missing piece’ in DNA repair spectrum disorders. While the relationship between pervasive developmental disorders and megalencephaly is well described, very few single gene disorders associated with this clinical relationship have been identified. Chapter four documents the discovery of two founder mutations in the KPTN gene associated with such a phenotype. The functional data shows that the encoded wild type molecule (kaptin) associates with dynamic actin cytoskeletal structures in cultured neurons and that the causative mutations result in loss of function perturbing this interaction, defining kaptin as a new molecule which is crucial for normal human brain development and function. 5 Chapter five details the investigation of the eponymously named “Hershberger syndrome”, a disorder originally described by McKusick in the Ohio Amish in 1967. Clinical and genetic studies of affected individuals revealed that the syndrome was comprised of two distinct disorders; Aicardi Goutières syndrome due to mutation in SAMHD1, and a new condition characterised by profound neurological impairment, cerebellar involvement and nephrosis. This condition, renamed “nephrocerebellar syndrome” was found to be caused by homozygous mutations in two closely linked genes, WHAMM and WDR73. The genetic and functional data supported the involvement of both molecules in the disease, suggesting that this is a composite phenotype. The identification and functional characterisation of three new genes responsible for abnormalities in brain growth provides an invaluable insight into disease pathogenesis and also identifies molecular pathways important for normal brain development. This is turn enables clinicians to provide a much needed diagnosis for affected individuals and their families as well as the wider community. 6 CONTENTS 1 INTRODUCTION ................................................................................... 26 1.1 Brain embryological development .......................................................... 26 1.1.1 Cerebral cortex ............................................................................................................... 28 1.1.2 Cerebellum ..................................................................................................................... 31 1.2 Abnormalities of brain growth ................................................................ 32 1.3 Occipitofrontal circumference ................................................................ 33 1.4 Microcephaly ......................................................................................... 35 1.4.1 Congenital Microcephaly ................................................................................................ 35 1.5 Megalencephaly .................................................................................... 37 1.6 Classification of intellectual disability ..................................................... 38 1.6.1 Developmental delay ...................................................................................................... 40 1.7 The Amish ............................................................................................. 43 1.7.1 History of the Windows of Hope project ......................................................................... 46 1.7.2 History of the Clinic for Special Children ........................................................................ 48 1.7.3 Disorders of brain growth and development identified amongst the Amish ................... 49 1.8 Autozygosity mapping ............................................................................ 54 1.9 Aims ....................................................................................................... 57 2 MATERIALS AND METHODS .............................................................. 60 2.1 Buffers, reagents and stock solutions .................................................... 60 2.2 Subjects and samples ............................................................................ 61 2.2.1 Recruitment to the Amish Windows of Hope (WOH) project ......................................... 61 2.2.2 Phenotyping of affected individuals ................................................................................ 61 2.3 Data management ................................................................................. 62 2.4 Molecular methods ................................................................................ 62 2.4.1 DNA extraction ............................................................................................................... 62 2.4.2 RNA extraction ............................................................................................................... 63 2.4.3 Single nucleotide polymorphism (SNP) genotyping ......................................................
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