Advances in Vision Research, Volume III: Genetic Eye Research around the Globe (Essentials in Ophthalmology)

This third volume, with three supporting editors, broadens its focus on genetic eye research from the Asian to the global scale. New efforts and a new awareness have sparked important discussions on genetic eye research, and new plans are being implemented to identify the genes responsible for numerous eye diseases. The book introduces the latest findings on genetics in eye diseases, gene therapy, and genome-wide association analysis, and the efforts of the Global Eye Genetic Consortium (GEGC). The book’s editors have been instrumental in developing strategies for discovering the new genes involved in many eye diseases. All chapters were written by leading researchers working on eye genetics from the fields of Human Genetics, Ophthalmology, Molecular Biology, Biochemistry, Sensory Sciences, and Clinical Research. Advances in Vision Research, Volume III is a major resource for all researchers, clinicians, clinical researchers, and allied eye health professionals with an interest in eye diseases around the globe. Foreword Preface: Recognizing the Special Year 2020 Acknowledgment Contents 1: Expansion of Asian Eye Genetics Consortium (AEGC) to Global Eye Genetics Consortium (GEGC), Introduction of a Global Phenotype-Genotype Database “GenEye” and Launch of New Training Programs at National Eye Institute (NEI) 1.1 Expansion of the Consortium from Asia to Global: Launch of the Global Eye Genetics Consortium (GEGC) 1.2 Launch of GEGC Phenotype-Genotype Database “GenEye” 1.3 The Updated Aim, Management, and Budget for GEGC 1.4 GEGC Lab Exchange Program for Young Scientists 1.5 GEGC as a Member of the International Council of Ophthalmology (ICO) 1.6 New International Training Programs/Fellowships in Genetic Eye Research at National Institutes of Health: National Eye Institute in the USA 1.6.1 New Program Launch: NEI-ICO Fellowship for International Fellows from Lower- and Middle-Income Countries (LMIC) 1.6.2 Expansion of International Genomics Fellowship at National Eye Institute in the USA 1.7 Updates on Other GEGC Sessions and Meetings During 2018 to 2019 1.7.1 GEGC Session at SAARC Academy of Ophthalmology 2018 1.7.2 GEGC Meeting at World Ophthalmology Congress 2018 1.7.3 Foundation of the GEGC China Branch 1.7.4 GEGC Session at Asia Pacific Academy of Ophthalmology 2019 2: Global Women’s Eye Health: A Genetic Epidemiologic Perspective 2.1 Current Review of Women’s Eye Health 2.2 Overall Global Blindness 2.2.1 Africa 2.2.2 Asia 2.2.3 Australia 2.2.4 Europe 2.2.5 North America 2.2.6 South America 2.3 Aging and Eye Disease in Women 2.4 Heritable Ocular Conditions 2.5 Pregnancy and the Eye 2.6 The Effects of the Stages of Menopause and the Eye 2.7 Climate Change and Women Eye Health 2.8 Approaches to Interventions 2.8.1 Telemedicine 2.8.2 Empowerment 2.8.3 Research 2.8.4 Initiatives 2.9 Conclusion Appendix Supplemental Tables References 3: Establishing the Chinese Arm of GEGC References 4: Human Material for Research: Eye Banking, Biobanking and Ethical Access 4.1 Introduction 4.2 Demand for Ocular Tissue in Research 4.3 About Eye and Biobanking 4.4 The Eye Bank 4.4.1 Factors Affecting the Availability of Research Tissue 4.4.2 Quality of Tissue 4.4.3 Quality of Clinical Documentation 4.4.4 Cost 4.5 The Biobank 4.5.1 Accessing Research Tissue (Models of Biobanks) 4.5.2 The Consent Process (Living and Cadaveric) 4.5.3 Legislation and Ethics 4.5.4 Barriers to Biobanking 4.6 Recommendations 4.7 Summary References 5: Current Understanding of Polypoidal Choroidal Vasculopathy 5.1 Introduction 5.2 Epidemiology and Global Perspective 5.3 Etiopathogenesis 5.4 Clinical Features 5.5 Genetic Aspects 5.6 Clinical 5.7 Summary References 6: Genetics of Age-Related Macular Degeneration in Asia 6.1 Before GWAS 6.2 GWAS 6.3 GWAS in Asia 6.4 Candidate Gene Analysis 6.5 Confirmed Association to AMD in Asians 6.6 New Treatments 6.7 AMD Subtypes 6.8 Phenotype-Genotype Associations 6.9 Personalized Medicine 6.10 Genes Associated with Pachychoroid Diseases References 7: The Contribution of Rare Allele and Junk Genome in AMD Pathogenesis 7.1 Biological Significance of Rare Alleles and Junk Genome 7.2 Mutation Threshold and Functional Diversification 7.3 Evolutionary Impact of Junk Genome in Complexity of Degenerative Diseases 7.4 Junk Genome and Biological Significance in AMD 7.5 Conclusion References 8: Differential Genotypes in Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy: A Updated Meta-Analysis 8.1 Introduction 8.2 Methods of Meta-Analysis 8.3 Results of Updated Meta-Analysis 8.4 Discussion 8.5 Summary References 9: Genetic Epidemiology of Quantitative Traits of Primary Open Angle Glaucoma 9.1 Intraocular Pressure 9.2 Central Corneal Thickness 9.3 Optic Disc Parameters 9.4 Retinal Nerve Fibre Layer Thickness 9.5 Integrating Endophenotypes with Glaucoma References 10: Association Studies on Retina Diseases in Chinese Population 10.1 Association Studies of Age-Related Macular Degeneration 10.2 Association Studies of Diabetic Retinopathy References 11: Congenital Stationary Night Blindness (CSNB): An Inherited Retinal Disorder Where Clear Correlations Can Be Made 11.1 Introduction 11.2 Epidemiology 11.3 Clinical Features 11.3.1 Riggs-Type of Congenital Stationary Night Blindness: A Form of Night Blindness with Largely Normal Fundus 11.3.2 Fundus Albipunctatus: A Form of Night Blindness with Fundus Abnormalities 11.3.3 Oguchi Disease: A Form of Night Blindness with Fundus Abnormalities 11.3.4 Schubert-Bornschein-Type of Congenital Stationary Night Blindness a Form of “Night Blindness” with Largely Normal Fundus 11.3.5 Incomplete Congenital Stationary Night Blindness 11.3.6 Complete Congenital Stationary Night Blindness 11.3.7 GNB3-CSNB 11.4 Molecular Biology 11.4.1 Gene Defects Implicated in Congenital Stationary Night Blindness 11.4.2 Gene Defects Underlying the Riggs-Type of Congenital Stationary Night Blindness, Fundus Albipunctatus, and Oguchi Disease 11.4.3 Gene Defects Underlying Incomplete Congenital Stationary Night Blindness 11.4.4 Gene Defects Underlying Complete Congenital Stationary Night Blindness 11.4.5 GNB3-Gene Defect 11.4.6 Laboratory 11.5 Summary References 12: Genome Analysis for Inherited Retinal Disease: The State of the Art 12.1 Background 12.2 Genetics of IRD 12.3 Genetic Screening Approaches 12.3.1 Targeted Gene Panels 12.3.2 Whole Exome Sequencing 12.3.3 Whole Genome Sequencing 12.4 Missing Heritability in Retinal Disease 12.5 Multiomics 12.6 Imaging, Genetics and Artificial Intelligence for Inherited Retinal Disease Analysis 12.7 Conclusions References 13: Generation and Analysis of Induced Photoreceptor-Like Cells from Fibroblasts of Patients with Retinitis Pigmentosa 13.1 Introduction 13.2 What Is “Redirect Differentiation”? 13.3 Methods of Differentiation and Assessment of Induced PR-Like Cells 13.4 Combinations of Transcription Factors Determining Photoreceptor Cell Fate 13.5 Endogenous and Exogenous Expression of Transcription Factors 13.6 Photo-Responsiveness of Induced PR-Like Cells 13.7 Variation of Cell Types of Sources for Induced PR-Like Cells (Fig. 13.1) 13.7.1 Iris 13.7.2 Dermal Fibroblasts 13.8 Peripheral Blood Mononuclear Cells (PBMCs) 13.9 Application of Induced PR-Like Cells to RP Research 13.10 Conclusion References 14: Genotype–Phenotype of RPE65 Mutations: A Reference Guide for Gene Testing and Its Clinical Application 14.1 Introduction 14.2 Methods 14.3 Results 14.3.1 Number of Publications and Patients 14.3.2 RPE65 Mutational Profile 14.3.3 Visual Acuity of Patients with RPE65 Mutations Decreases with Age 14.3.4 Fundus Features of RPE65 Mutated Patients 14.3.5 Genotype–Phenotype Correlations 14.3.6 The Global Distribution of Families with Biallelic RPE65 Mutations and Genotypic/Phenotypic Differences Among Different Ethnic Groups 14.4 Discussion References 15: Genetic Variants and Impact in PDE6B Rod-Cone Dystrophy 15.1 Introduction 15.2 Materials and Methods 15.3 PDE6B Variants 15.3.1 Spectrum of PDE6B Variants 15.3.2 Pathogenicity Assessment of PDE6B Variants 15.3.3 Genotype–Phenotype Correlation 15.3.4 Future Directions 15.4 Conclusion References 16: The Retinitis Pigmentosa Genes 16.1 Introduction 16.2 Genes Involved in RP 16.3 The Phototransduction Cascade 16.4 The Visual Cycle 16.5 Ciliary Structure and Transport References 17: Primary Congenital Glaucoma Genetics: The Experience in Brazil 17.1 Introduction 17.2 Epidemiology 17.3 Mechanisms and Clinical Features 17.4 Genetic Aspects 17.4.1 CYP1B1 Gene Screening in Brazilian PCG Patients 17.5 Summary References 18: Glaucoma Genetics in Pakistan 18.1 Introduction 18.2 Global Perspective 18.3 Epidemiology 18.4 Etiology 18.5 Experimental 18.5.1 Identification of Novel Genes, Loci, and Novel Mutations in Known Genes 18.5.1.1 Homozygosity Mapping and Exome Sequencing 18.5.1.2 Genome Wide Association Studies 18.6 Genetic Aspects 18.6.1 Familial Glaucoma Genetics in Pakistan 18.6.1.1 CYP1B1 Associated Glaucoma Families 18.6.2 Other Genes Involved in Familial Glaucoma 18.6.3 Genetics of Glaucoma Syndromes 18.6.4 Genetics of Sporadic Glaucoma 18.7 Pathology and Clinical Features 18.7.1 Genotype–Phenotype Correlation 18.8 Molecular Biology 18.8.1 Molecular Biology of Familial Glaucoma in Pakistan 18.8.2 Molecular Biology of Sporadic Glaucoma in Pakistan 18.9 Summary References 19: Contributions of Promoter Variants to Complex Eye Diseases 19.1 Introduction 19.2 Myopia 19.2.1 Paired Box 6 Gene 19.2.2 Lumican Gene 19.2.3 Extracellular Matrix-Related Genes 19.2.4 Other Genes 19.3 Age-Related Macular Degeneration 19.3.1 Complement Factor H Gene 19.3.2 High Temperature Requirement Factor A1 Gene 19.3.3 Tumor Necrosis Factor Receptor Superfamily Member 10A Gene 19.3.4 Lipase C Gene 19.3.5 Other Genes 19.4 Glaucoma 19.4.1 Myocillin Gene 19.4.2 Cytochrome P450 Family 1 Subfamily B Member 1 Gene 19.4.3 Caveolin-1 Gene 19.4.4 Cyclin-Dependent Kinase Inhibitor 2B Gene 19.4.5 Lysyl Oxidase-Like 1 Antisense RNA 1 Gene 19.4.6 Apolipoprotein E Gene 19.4.7 Inflammation-Related Genes 19.4.8 Nitric Oxide Synthase Genes 19.4.9 Matrix Metalloproteinase Genes 19.4.10 Other Genes 19.5 Cataract 19.5.1 Crystallin-α A Gene 19.5.2 Crystallin-γ B Gene 19.5.3 Ferritin Light Chain Gene 19.5.4 Transmembrane Protein 114 Gene 19.5.5 Ras Related GTP Binding A Gene 19.5.6 Other Genes 19.6 Summary and Future Perspectives References 20: Vascular Basement Membrane Thickening: Basis of Disease Pathology in Diabetic Retinopathy 20.1 Introduction 20.1.1 Structure and Biological Function of the BM 20.1.2 Structure and Components of the BM 20.1.3 Other BM Components 20.1.4 Assembly of BM Components 20.1.5 BM Stiffness 20.2 Biological Function of the BM 20.2.1 Selective Permeability Barrier 20.2.2 Substratum for Cell Attachment 20.2.3 Apoptosis 20.2.4 The BM Influences Retinal Blood Flow 20.2.5 The BM Regulates Neovascularization 20.3 Regulation of Cell Signaling via Integrin and Cell–Matrix Interactions 20.4 How Does Thickened Vascular BM Develop in Diabetic Retinas? 20.4.1 Overexpression of BM Components 20.4.2 Effect of Polyol Pathway 20.4.3 Activation of Protein Kinase C 20.4.4 Advanced Glycation End Products 20.4.5 Role of BM Thickening in Disease Pathology 20.5 Treatment and Prevention Measures References 21: Molecular Genetics and Clinical Aspects of Macular Corneal Dystrophy 21.1 Introduction 21.2 History of Macular Corneal Dystrophy 21.3 Macular Corneal Dystrophy 21.4 Epidemiology and Demographics of MCD 21.5 Biochemical Mechanism of MCD 21.6 Clinical Manifestations 21.7 Immunophenotypes of MCD 21.8 Genetics of MCD 21.9 Imaging 21.10 Treatment 21.11 Recurrence 21.12 Newer Treatment Options 21.13 Conclusion References 22: Congenital and Inherited Cataracts 22.1 Introduction 22.2 Epidemiology and Global Perspective 22.3 Etiology 22.4 Transcription and Developmental Factors 22.5 Lens Crystallins 22.6 Gap Junction Proteins (Connexins) 22.7 Membranes and Their Proteins 22.8 Beaded Filament and Other Intermediate Filament Proteins 22.9 Chaperones and Protein Degradation 22.10 Other Genes and Pathways 22.11 Pathology 22.12 Clinical Features and Classification of Congenital Cataracts 22.13 Genetic Aspects of Congenital Cataracts 22.14 Clinical Aspects of Congenital Cataracts 22.15 Molecular Biology of Congenital Cataracts 22.16 Laboratory and Clinical Evaluation of Congenital Cataracts 22.17 Summary References 23: Higher Order Aberrations: Differences Among Populations from Various Demographics 23.1 Introduction 23.2 Basics of Ocular Higher Order Aberrations 23.3 Factors Affecting Wavefront Capture 23.4 Need for Normative Databases of Higher Order Aberrations 23.5 Population-Based Variations in Higher Order Aberrations 23.5.1 Caucasian/American Demographics 23.5.2 Asian Population (Chinese and Indian Subcontinental) 23.5.3 Middle Eastern Population 23.6 Conclusion References 24: Genetics of Microphthalmia: Global and Indian Perspectives 24.1 Introduction 24.2 Clinical Diagnosis and Classification of Microphthalmia 24.2.1 Diagnosis of Microphthalmia 24.2.1.1 Gross Clinical Examination 24.2.1.2 Imaging Techniques 24.2.2 Classification of Microphthalmia 24.3 Etiology of Microphthalmia 24.4 Molecular Genetic Mechanism of Normal Eye Development 24.4.1 Formation of Eye Field 24.4.2 Patterning of Neural Plate 24.4.3 Separation of Eye Field 24.4.4 Formation of the Neural Tube and Optic Vesicle 24.4.5 Formation of the Optic Cup and Lens Placode 24.4.6 Formation of Retinal Pigment Epithelium and Neural Retina 24.4.7 RPE Specification 24.4.8 Neural Retina Specification 24.4.9 Formation of Lens and Other Ocular Structures 24.5 Genetics of Microphthalmia: Indian and Global Perspectives 24.5.1 Genetic Studies on Microphthalmia: Global Perspectives 24.5.1.1 BMP4 Gene and Microphthalmia 24.5.1.2 FOXE3 Gene and Microphthalmia 24.5.1.3 OTX2 Gene and Microphthalmia 24.5.1.4 PITX3 Gene and Microphthalmia 24.5.1.5 RAX Gene and Microphthalmia 24.5.1.6 SIX6 Gene and Microphthalmia 24.5.1.7 SOX2 Gene and Microphthalmia 24.5.1.8 VSX2 (Visual System Homeobox 2) Gene and Microphthalmia 24.5.2 Genetic Studies on Microphthalmia: Indian Perspectives 24.5.2.1 SOX2 Gene and Microphthalmia 24.5.2.2 Gap Junction Proteins: Novel Candidates of Microphthalmia GJA3 (Gap Junction Alpha 3) Gene Mutation and Microphthalmia GJA8 (Gap Junction Alpha 8) Gene Mutation and Microphthalmia 24.6 Summary and Conclusion 24.7 Future Perspectives References 25: Regional Differences in Prevalence of Myopia: Genetic or Environmental Effects? 25.1 Introduction 25.2 Prevalence 25.2.1 Variation with Urbanization 25.2.2 Variation with Ethnicity 25.3 Genetic Factors 25.3.1 Ocular Endophenotypes of Myopia 25.3.2 Inheritance Pattern 25.4 Environmental Factors 25.4.1 Education 25.4.2 Near Work and Hyperopic Defocus 25.4.3 Time Spent Outdoors 25.5 Gene−Environment Interaction 25.6 Summary References 26: Consortium for Refractive Error and Myopia (CREAM): Vision, Mission, and Accomplishments 26.1 Key Points 26.2 Introduction 26.3 Heritability 26.4 Linkage Studies 26.5 Secondary Syndromic Myopia 26.6 Candidate Gene Studies 26.7 Genome-Wide Association Studies (GWAS) 26.7.1 GWAS of Refractive Errors and Myopia 26.7.1.1 Myopia Case–Control Design 26.7.1.2 Quantitative Design on Spherical Equivalent 26.7.1.3 GWAS on Refractive Error Endophenotypes 26.7.2 Genome-Wide Pathway Analyses 26.7.3 Astigmatism 26.8 Whole-Exome and Whole-Genome Sequencing 26.9 Gene–Environment Interaction 26.10 Mendelian Randomization 26.11 Epigenetics 26.12 Concluding Remarks CREAM Membership List The CREAM Consortium References 27: Oncologic Properties of Retinoblastoma Genes 27.1 RB1 Inactivation in Hong Kong Chinese Retinoblastoma Patients 27.2 RASSF1A Inactivation in Hong Kong Chinese Retinoblastoma Patients 27.3 MGMT Inactivation in Hong Kong Chinese Retinoblastoma Patients 27.4 MLH1 Inactivation in Hong Kong Chinese Retinoblastoma Patients 27.5 Novel Functions of RB in Genome Stability 27.6 Conclusive Remarks References 28: Oncologic Implications of Genetic and Epigenetic Basis of Pterygium 28.1 Oncologic Implications of Genetic Basis of Pterygium 28.1.1 p53 and MDM2 Expression in Pterygium 28.1.2 p53 and MDM2 Expression in Conjunctiva 28.1.3 Nutlin as a Novel Treatment to Pterygium 28.1.4 Growth Hormone-Releasing Hormone Signaling Pathway in Pterygium 28.2 Cigarette Smoking on Pterygium Development and Progression 28.2.1 The Effect of Nicotine and Its Metabolites on Human Primary Pterygium Cells 28.2.2 The Mechanistic Regulations of Nicotine and Its Metabolites on Human Primary Pterygium Cells 28.2.3 Implication of Nicotine and Its Metabolites on Human Primary Pterygium Cell Development and Progression 28.3 Conclusive Remarks References 29: The Need for Alternative Therapies in Eye Disorders 29.1 Introduction 29.2 Current Treatment 29.3 Pitfalls of Current Treatment Modalities 29.4 Failed Clinical Trials 29.5 Evidence-Based Alternative Treatment Options in Eye Diseases 29.5.1 Herbal Based Alternative Therapies 29.5.2 Yoga Based Alternative Therapy for Vision Related Issues 29.5.3 Stem Cell Therapy as Alternative Approach and Its Complications 29.6 Ambiguous Genetic Analysis: Limitation of Current Reductionist Approach 29.6.1 Ayurgenomics and Development of Personalized Medicine 29.7 Summary References 30: Gene Therapy for Retinal Diseases 30.1 Introduction 30.2 Recombinant Adeno-Associated Virus Vectors in Retinal Gene Therapy 30.2.1 Serotypes for Retinal Cell Transduction 30.2.2 Broadly Active Versus Specific Promoters 30.2.3 Injection Methods 30.2.4 Immune Responses, Bio-distribution, and Cellular Toxicity 30.3 Alternate Methods of Gene Delivery 30.4 Gene Therapy of Congenital Retinal Degenerations 30.4.1 Retinitis Pigmentosa (Rod–Cone Dystrophies) 30.4.2 Cone–Rod Dystrophies 30.4.3 LCA 30.4.4 Stargardt Disease 30.4.5 X-Linked Juvenile Retinoschisis 30.5 Gene Therapy of Retinal Neovascularization 30.6 Gene Therapy of Syndrome-Associated Retinal Degenerations 30.7 Conclusion References 31: The Use of Human Pluripotent Stem Cells (hPSCs) and CRISPR-Mediated Gene Editing in Retinal Diseases 31.1 Current Models for Eye Disease 31.1.1 Human Pluripotent Stem Cells 31.2 Retinal Development 31.2.1 Differentiation of PSCs into RPE Cells 31.2.2 Differentiation of hPSCs to Neural Retina Using an Adherent Model 31.2.3 Three-Dimensional Retinal Organoids to Yield Retinal Progenitors and Mature Retinal Neurons 31.3 Gene Editing in Retinal Degenerative Diseases 31.3.1 Clustered Regularly Interspaced Short Palindromic Repeats (CRIPSR)/Cas System 31.3.2 Gene Editing of PSCs with CRISPR/Cas 31.3.3 In Vivo and Clinical Application of CRISPR/Cas System 31.4 Summary References About the Editors Index This book presents the state of the art in genetic eye research in Asia and the Pacific. Though there has been an explosion of information on genetic eye research in western countries, more than sixty percent of the human genes involved in eye diseases in the Asian and Pacific population remain unknown. However, new efforts and a new awareness have sparked important discussions on the subject, and new plans are being implemented to discover the genes responsible for many eye diseases in the population. The book reviews the latest findings; its content ranges from genetic aspects of human migration to DNA sequence analysis, genome-wide association analysis, and disease phenotypes. The efforts of the Asian Eye Genetic Consortium (AEGC) are also discussed. The book's editors have been instrumental in developing strategies for discovering the new Asian genes involved in many eye diseases. All chapters were written by leading researchers working on Asian eye genetics from the fields of Human Genetics, Ophthalmology, Molecular Biology, Biochemistry, Sensory Sciences, and Clinical Research. Advances in Vision Research, Volume I will prove to be a major resource for all researchers, clinicians, clinical researchers, and allied eye health professionals with an interest in eye diseases among the Asian population