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Molecular Genetics and Genotype-Phenotype Correlation Of Molecular genetics and genotype-phenotype correlation of inherited corneal dystrophies Cerys J. Evans University College London Doctor of Philosophy (PhD) Supervisors: Professor Alison Hardcastle and Mr. Stephen Tuft Declaration I, Cerys J. Evans, 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. 2 Publications Evans, C.J., Liskova, P., Dudakova, L., Hrabcikova, P., Horinek, A., Jirsova, K., Filipec, M., Hardcastle, A., Davidson, A. and Tuft, S. (2015) ‘Identification of six novel mutations in ZEB1 and description of the associated phenotypes in patients with posterior polymorphous corneal dystrophy 3.’, Annals of Human Genetics, 79(1), pp. 1–9. Liskova, P., Evans, C. J., Davidson, A. E., Zaliova, M., Dudakova, L., Trkova, M., Stranecky, V., Carnt, N., Plagnol, V., Vincent, A. L., Tuft, S. J. and Hardcastle, A. J. (2015) ‘Heterozygous deletions at the ZEB1 locus verify haploinsufficiency as the mechanism of disease for posterior polymorphous corneal dystrophy type 3.’, European Journal of Human Genetics, 24(7), pp. 985–991. Davidson, A., Liskova, P., Evans, C.J., Dudakova, L., Nosková, L., Pontikos, N., Hartmannová, H., Hodaňová, K., Stránecký, V., Kozmík, Z., Levis, H., Idigo, N., Sasai, N., Maher, G., Bellingham, J., Veli, N., Ebenezer, N., Cheetham, M., Daniels, J., Thaung, C., Jirsova, K., Plagnol, V., Filipec, M., Kmoch, S., Tuft, S. and Hardcastle, A. (2015) ‘Autosomal-dominant corneal endothelial dystrophies CHED1 and PPCD1 are allelic disorders caused by non-coding mutations in the promoter of OVOL2.’, The American Journal of Human Genetics, 98(1), pp. 75–89. Evans, C. J., Davidson, A. E., Carnt, N., Rojas López, K. E., Veli, N., Thaung, C. M., Tuft, S. J. and Hardcastle, A. J. (2016) ‘Genotype-phenotype correlation for TGFBI corneal dystrophies identifies p.(G623D) as a novel cause of epithelial basement membrane dystrophy.’, Investigative Ophthalmology & Visual Science, 57(13), pp. 5407–5414. Morantes, S., Evans, C. J., Valencia, A. V, Davidson, A. E., Hardcastle, A. J., Linares, A. R., Tuft, S. J. and Cuevas, M. (2016) ‘Spectrum of clinical signs and genetic characterization of gelatinous drop-like corneal dystrophy in a Colombian family.’, Cornea, 35(8), pp. 1141–11466. 3 Acknowledgements I would like to thank my supervisors, Prof. Alison Hardcastle and Mr. Stephen Tuft, for providing me with the opportunity to undertake this project and for guiding me through the PhD process. I could not have completed this thesis without their unwavering support. I would like to thank all my colleagues at the Institute of Ophthalmology for providing both technical and emotional support throughout the PhD, particularly, Alice Davidson, Sek-Shir Cheong, Naheed Kanuga, Wenwen Li, Nikolas Pontikos, Jessica Gardner and Michael Cheetham. I would also like to thank my collaborator Petra Liskova. I would like to thank Fight for Sight who generously provided the funding for this project. Most importantly, I would like to thank the patients and relatives who donated their samples, without which this project could not have been completed. I hope that the results within this thesis have a positive impact and will contribute to the development of therapies in future. Finally, I would like to thank my family and friends who encouraged me to keep going. 4 Abstract Corneal dystrophies are a group of inherited, primarily monogenic, disorders that compromise the transparency of the cornea and cause visual impairment. A large cohort, consisting of 191 corneal dystrophy probands, was recruited to the study with the aim of investigating the genetic basis of phenotypically heterogeneous corneal dystrophy diagnoses. Following genetic investigation, genotype data was combined with clinical data to investigate genotype-phenotype correlations. The most common cause of corneal dystrophy in this cohort was heterozygous dominant mutations in TGFBI, which were identified in 70 probands with epithelial- stromal dystrophies. The majority of TGFBI mutations displayed genotype- phenotype correlation, however a p.(Gly623Asp) mutation was unexpectedly associated with a broad phenotypic spectrum of disease, including epithelial basement membrane dystrophy (EBMD). There was evidence for additional locus heterogeneity for EBMD; two families were identified in which TGFBI coding mutations were excluded, however no compelling candidate gene(s) were identified following whole exome sequence (WES) analysis. Novel and previously reported mutations in CHST6, UBIAD1 and TACTSD2 were identified for other anterior corneal dystrophies; recessive macular corneal dystrophy, dominant Schnyder corneal dystrophy and recessive gelatinous drop-like dystrophy, respectively. Dominant mutations in ZEB1 were identified in 8 patients with an endothelial dystrophy, posterior polymorphous corneal dystrophy (PPCD3), with novel heterozygous deletions encompassing the ZEB1 gene confirming haploinsufficiency as the mechanism of pathogenicity. 5 Investigation of dominant endothelial dystrophy families using whole genome sequencing (WGS), including PPCD1 and congenital hereditary endothelial dystrophy (CHED1), revealed that mutations in the promoter of OVOL2 are a novel cause of disease and therefore that PPCD1 and CHED1 are allelic disorders. OVOL2 is a transcription factor, which is a direct repressor of ZEB1. OVOL2 was not expressed in normal corneal endothelial cells, therefore it was hypothesised that aberrant expression of OVOL2 in corneal endothelial cells causes transcriptional repression of ZEB1 expression. A novel locus causing dominant PPCD (PPCD4) was identified in a large family from the Czech Republic and linkage analysis and WGS revealed a non-coding mutation in a novel gene as likely to be causative in this family. Interestingly, a proportion of patients clinically diagnosed with a corneal dystrophy were found, on further genetic and clinical investigation, to have an inherited syndrome which was responsible for the presence of corneal opacities, the most common of which was Meretoja syndrome. In some cases, a phenocopy of disease was responsible, including paraproteinemic keratopathy. Genetic screening can therefore significantly improve clinical care for patients and their families. In summary, this study provides insight into the genetic causes of corneal dystrophies including the identification of novel corneal dystrophy genes and mechanisms of disease, which is a pre-requisite for the development of targeted genetic therapies. Furthermore, it provides further understanding of genotype- phenotype correlation for specific corneal dystrophy genes and mutations that can result in improved diagnostic and prognostic accuracy for patients. 6 Contents ABSTRACT 5 LIST OF FIGURES 16 CHAPTER 1: INTRODUCTION 30 1.1 Anatomy of the eye 30 1.2 Structure and function of the cornea 31 1.2.1 Epithelium 32 1.2.2 Bowman’s layer 32 1.2.3 Stroma 32 1.2.4 Descemet’s membrane 33 1.2.5 Endothelium 33 1.2.6 Dua’s layer 34 1.2.7 Corneal nerves 34 1.3 Corneal development 35 1.3.1 Anterior segment development 35 1.3.2 Epithelial development 36 1.3.3 Development of the corneal stroma and endothelium 36 1.4 Corneal homeostasis and wound healing 38 1.4.1 Epithelial homeostasis 38 1.4.2 Stromal homeostasis 39 1.4.3 Epithelium and stromal wound healing 40 1.4.4 Endothelial homeostasis 41 1.4.5 Endothelium wound healing 41 1.5 Corneal dystrophies 41 1.5.1 Overview 41 1.5.2 Clinical diagnosis 42 1.5.3 Management options 43 7 1.6 Genetic techniques 46 1.6.1 Linkage analysis 46 1.6.2 Sanger sequencing 48 1.6.3 Next-generation sequencing 48 1.6.4 Identification of copy number variation 53 1.7 Genetics of corneal dystrophies 55 1.7.1 Anterior corneal dystrophies 55 1.7.2 Endothelial corneal dystrophies 56 1.8 The IC3D classification of corneal dystrophies 57 1.9 Aims of project 61 CHAPTER 2: MATERIALS AND METHODS 63 2.1 Patient recruitment and sample collection 63 2.1.1 Clinical diagnosis 63 2.1.2 Clinical histology 63 2.1.3 DNA extraction from blood 63 2.1.4 DNA extraction from saliva 64 2.1.5 Obtaining DNA samples from additional sites 64 2.2 Sanger sequencing 64 2.2.1 Primer design 64 2.2.2 Polymerase chain reaction 65 2.2.3 Agarose gel electrophoresis 67 2.2.4 PCR purification 67 2.2.5 Sanger sequencing 68 2.3 Assessment of variant pathogenicity 69 2.3.1 Frequency 69 2.3.2 Amino acid conservation 69 2.3.3 Pathogenicity prediction tools 69 2.3.4 Segregation analysis 70 2.3.5 Splice prediction tools 70 8 2.3.6 Transcription factor binding predictions 70 2.4 STS deletion screening 71 2.5 CHST6 deletion and rearrangement screening 71 2.6 Whole exome sequencing 71 2.6.1 Alignment of read data and variant calling 72 2.6.2 Variant filtering strategies of WES data 72 2.6.3 Exome depth 73 2.7 SNP array genotyping for copy number variations 74 2.8 ZEB1 deletion quantitative PCR assay 74 2.8.1 Primer design 74 2.8.2 qPCR reactions 74 2.8.3 qPCR data analysis 75 2.9 ZEB1 deletion breakpoint mapping 75 2.10 Linkage analysis 76 2.11 Whole genome sequencing 76 2.11.1 Alignment of read data and variant calling 77 2.11.2 Variant filtering of WGS data 77 2.11.3 Variant effect predictor 77 2.12 Culturing corneal derived cells 78 2.12.1 Isolation and culturing stromal fibroblasts 78 2.12.2 Culturing limbal epithelial cells 78 2.12.3 Culturing immortalised human corneal epithelial cells 79 2.13 Reverse-transcription PCR 79 2.13.1 RNA extraction from cells 79 2.13.2 cDNA synthesis 79 2.13.3 RT-PCR to investigate
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