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Molecular Pathology of Autosomal Recessive Retinal Disease

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Molecular Pathology of Autosomal Recessive Retinal Disease UCL INSTITUTE OF OPHTHALMOLOGY LONDON Genetic and phenotypic heterogeneity in autosomal recessive retinal disease Panagiotis Sergouniotis Institute of Ophthalmology, University College London Submitted to the University College of London for the Degree of Doctor of Philosophy April 2012 Supervisors: Dr Andrew R Webster Professor Anthony T Moore DECLARATION DECLARATION I, Panagiotis Sergouniotis, 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. Panagiotis I Sergouniotis 1 ABSTRACT ABSTRACT Molecular genetics has transformed our understanding of disease and is gradually changing the way medicine is practiced. Genetic mapping provides a powerful approach to discover genes and biological processes underlying human disorders. Recent advances in DNA microarray and sequencing technology have significantly increased the power of genetic mapping studies and have ushered in a new era for biomedicine. In this thesis, linkage analysis (including homozygosity mapping), exome sequencing and candidate gene sequencing have been utilised to genetically dissect autosomal recessive retinal disease. Subsequently, clinical findings from patients found to be similar in terms of molecular pathology have been pooled. DNA and basic phenotypic data from over 500 unrelated individuals were available for the project. Disease-causing variants in three genes that have not been previously associated with human recessive disorders are reported: (a) biallelic mutations in TRPM1 abrogate ON bipolar cell function and cause complete congenital stationary night blindness; (b) biallelic mutations in KCNJ13, a gene encoding an inwardly rectifying potassium channel subunit cause Leber congenital amaurosis; (c) biallelic mutations in PLA2G5, a gene encoding group V phospholipase A2, cause benign fleck retina. The consequences of mutations in these and other disease-related genes (RDH5, GRM6, KCNV2, OAT and SAG) on retinal structure (spectral domain optical coherence tomography, fundus autofluorescence imaging) and visual function (electrophysiology, perimetry testing) have been studied; features that may have mechanistic relevance have been identified. Additionally, DNA sequence variation of a highly polymorphic gene (C2ORF71), recently associated with photoreceptor degeneration, has been studied and quantified in patient and control samples. Basic bioinformatics tools to analyse genomic data have been developed (bash, perl, python and R programming languages). Overall, results presented in this thesis contribute to an understanding of Mendelian retinal disease that is not only observational but also mechanistic. 2 ACKNOWLEDGEMENTS ACKNOWLEDGEMENTS I would like to thank my supervisors Dr Andrew Webster and Professor Tony Moore for giving me the opportunity to undertake this project and for the unconditional trust they bestowed upon me over the last three years. They have been an inspiration to pursue a career in ophthalmic genetics. Special thanks to Dr Zheng Li, Dr Alice Davidson, Dr Donna Mackay and all the members of the Webster/Moore research group, past and present, for their encouragement, help and scientific guidance. I am grateful to Professor Graham Holder and Dr Tony Robson for their collaborative inputs and for introducing me to retinal electrophysiology. I am greatly indebted to Dr Vincent Plagnol for the very fruitful and fun collaboration; his kindness, high quality of expertise, collaborative spirit and general enthusiasm for science made working with him a joy. I would like to thank the Markideion Foundation, the Alexander S. Onassis Foundation, the British Retinitis Pigmentosa Society (RP Fighting Blindness), the Special Trustees of Moorfields Eye Hospital and the National Institute for Health Research UK (Moorfields Eye Hospital and UCL Institute of Ophthalmology Biomedical Research Centre) for the financial support. I wish to thank my friend Thomas Daskalakis for his help with python programming and for introducing me to computational thinking. I also wish to express my gratitude to the families that contributed to the study. It has been a great pleasure to meet them in clinic and they have been a genuine source of inspiration to me. Finally, I wish to dedicate this thesis to my family (Efi, Ilias, Angeliki, yiayia Foteini) and especially to my brother Fotis for paving the way. 3 TABLE OF CONTENTS TABLE OF CONTENTS DECLARATION ................................................................................................ 1 ABSTRACT ....................................................................................................... 2 ACKNOWLEDGEMENTS ................................................................................. 3 TABLE OF CONTENTS .................................................................................... 4 LIST OF FIGURES ........................................................................................... 6 LIST OF TABLES.............................................................................................. 9 ABBREVIATIONS ........................................................................................... 11 1 INTRODUCTION ..................................................................................... 14 1.1 Genetics ........................................................................................... 14 1.1.1 A Brief History of Genes and Linkage ....................................... 14 1.1.2 Molecular Medicine: from Phenotype to Genomic Variation ...... 26 1.1.3 Hereditary Disease and the Eye ................................................ 29 1.2 The Retina ........................................................................................ 30 1.2.1 The Retinal Pigment Epithelium ................................................ 30 1.2.2 The Neurosensory Retina .......................................................... 33 1.2.3 Non-neuronal Elements ............................................................. 36 1.3 Inherited Retinal Disease ................................................................. 37 1.3.1 Clinical Diagnosis ...................................................................... 39 1.3.2 Electrophysiology ...................................................................... 39 1.3.3 Retinal Imaging ......................................................................... 41 1.4 Aims of this Thesis ........................................................................... 47 2 MATERIALS AND METHODS ................................................................. 48 2.1 Study Subjects .................................................................................. 48 2.1.1 Ethical Approval and Consent ................................................... 48 2.1.2 Control Panels ........................................................................... 48 2.1.3 Linkage Study ............................................................................ 48 2.1.4 Exome Sequencing Study ......................................................... 50 2.1.5 Mutation Detection Study .......................................................... 50 2.2 Phenotyping ...................................................................................... 52 2.3 Bacteriological Procedures ............................................................... 54 2.3.1 Bacterial Strain .......................................................................... 54 2.3.2 Transformation of Chemically Competent Cells ........................ 54 2.3.3 Preparation of Growth Medium for Blue/White Screen .............. 54 2.3.4 Screening Bacterial Colonies and Bacterial Culture Growth ...... 55 2.4 Nucleic Acid Procedures .................................................................. 55 2.4.1 RNA Electrophoresis ................................................................. 56 2.4.2 Reverse Transcription ............................................................... 57 2.4.3 DNA Extraction .......................................................................... 57 2.4.4 Quantification of DNA ................................................................ 58 2.4.5 Ethanol Precipitation of DNA ..................................................... 58 2.4.6 Digestion of DNA ....................................................................... 59 2.4.7 Ligation of DNA ......................................................................... 60 2.4.8 Agarose Gel Electrophoresis ..................................................... 60 2.4.9 PCR ........................................................................................... 61 2.4.10 Amplification Refractory Mutation System ................................. 62 2.4.11 Multiplex Ligation-dependent Probe Amplification ..................... 63 4 TABLE OF CONTENTS 2.4.12 Rapid Amplification of 5' and 3' cDNA Ends .............................. 63 2.4.13 Cloning PCR Products into T Vectors ....................................... 65 2.4.14 Purification of PCR Products and Plasmid DNA ........................ 66 2.4.15 High Resolution Melting Analysis .............................................. 66 2.4.16 DNA Sequencing Using Sanger Method ................................... 68 2.4.17 Targeted Capture and High-throughput DNA Sequencing ........ 68 2.4.18 DNA Microarrays ....................................................................... 71 2.4.19 Microsatellite Markers ...............................................................
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