Retinal Disorders: Genetic Approaches to Diagnosis and Treatment

This is a free sample of content from Retinal Disorders: Genetic Approaches to Diagnosis and Treatment. Click here for more information or to buy the book.

Index

A linkage structure, 186–188 AAV. See Adeno-associated virus nature of variation, 185 ABCA4 overview, 181–182 age-related macular degeneration susceptibility pathogenesis and pathophysiology, 184 studies, 161–162 prospects, 188–189 allele frequency, 48 risk prediction, 186 gene therapy techniques for study, 182–184 adeno-associated virus vectors, 291–293 variant frequency and effect magnitude, lentivirus vectors, 293–294 184–185 overview, 289–290, 429 clinical features plasmid vectors, 290–291 early and intermediate disease, 111 prospects, 294 geographic atrophy, 112–114 genetic modifiers, 61–62 neovascular disease, 113–116 induced pluripotent stem cell modeling of normal aging, 110–111 diseases, 92–93 overview, 109–110, 128, 182 Stargardt disease mutations, 9, 42, 289 polyploidal choroidal vasculopathy, 116–117 Abetalipoproteinemia. See Bassen–Kornzweig reticular pseudodrusen, 112 syndrome retinal angiomatous proliferation, 117 Achromatopsia drusen. See Drusen clinical features, 11 gene expression studies gene mutations, 11 DNA microarrays, 174–176 neuroprotection, 15 factors affecting gene expression Adeno-associated virus (AAV), gene therapy vectors epigenetics, 173–174 ABCA4 delivery, 291 genetic variation, 172–173 angiostatin delivery, 314–315 splice variants, 173 CHM delivery, 281–285 resources, 170 MYO7A delivery RNA-Seq, 174–176 dual vectors, 304–305 sample considerations, 171–172 single vectors, 303–304 gene therapy for neovascular disease overview, 12–14 angiostatin, 314–315 PRPH2 delivery, 352–354 endostatin, 314–315 RHO delivery, 389–391 pigment epithelium-derived factor, 313–314 RPE65 delivery, 260, 263–265, 282, 427–430 prospects, 315 RPGR delivery, 276–382 vascular endothelial growth factor RS1 delivery, 337–341, 343 inhibitors, 310–312 sFLT delivery, 311–313 genome-wide association studies in susceptibility Adenovirus, gene therapy vector for PEDF delivery, ARMS2, 129, 134 313–314 BF, 132 Advanced glycation end products (AGEs), drusen, C2, 132, 134 147–148 C3, 133, 135 Afliberept, age-related macular degeneration C5, 133 management, 121 C9, 135 Age-related macular degeneration (AMD) CFB, 134 classification, 109, 169, 182 CFD, 133 clinical application of genetics studies CFG, 133 classification and subtyping of disease, 186–187 CFH, 129–134 drug development, 187–188 CFHR genes, 132

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© 2015 by Cold Spring Harbor Laboratory Press. All rights reserved. This is a free sample of content from Retinal Disorders: Genetic Approaches to Diagnosis and Treatment. Click here for more information or to buy the book. Index

Age-related macular degeneration ARMS2 (AMD) (Continued) age-related macular degeneration susceptibility CFI, 133, 135 studies, 129, 134, 156 CFP, 133 induced pluripotent stem cell modeling genetic risk scores, 136–137 of mutation, 95 HTRA1, 129, 134 meta-analysis of studies, 134–135 B PLEKHA1, 129 Bardet–Biedl syndrome (BBS) prospects, 135–136 clinical features, 103 highly penetrant alleles gene mutations, 46 ARMS2, 155–156 genetic modifiers, 59, 62, 65 CFH, 155–156, 159–161 retinitis pigmentosa, 6 HTRA1, 155–156 Basal laminar deposits (BLamD), age-related macular overview, 155–157 degeneration, 111 rare variants Bassen–Kornzweig syndrome (BKS), clinical ABCA4, 161–162 features, 103 C3, 158–159 BBS. See Bardet–Biedl syndrome C9, 159 BCD. See Bietti’s crystalline retinal dystrophy candidate gene analysis, 157–158 BDNF. See Brain-derived neurotrophic factor CFI, 161 BEST1, induced pluripotent stem cell modeling clinical subtypes, 164 of mutation, 94 exome chip analysis, 158 b-Carotene, age-related macular degeneration exome sequencing, 158 management, 118 FBLN5, 162 Bevacizumab, age-related macular degeneration HMCN1, 163 management, 121 linkage analysis, 157 BF, age-related macular degeneration susceptibility predictive testing, 163–164 studies, 132 prospects for study, 164–165 Bietti’s crystalline retinal dystrophy (BCD), clinical whole genome sequencing, 158 features, 104 induced pluripotent stem cell modeling, 94–95 Bimatoprost, glaucoma management, 201 risk factors, 110, 128–129, 170 BKS. See Bassen–Kornzweig syndrome RNA-Seq studies, 83–84 BLamD. See Basal laminar deposits treatment Brain-derived neurotrophic factor (BDNF), neovascular disease neuroprotection, 15 afliberept, 121 BrainPort, 18 bevacizumab, 121 combination therapy, 121 macular surgery, 119–120 C pegaptanib, 120 CABP4, congenital stationary night blindness photocoagulation, 119 mutations, 10 photodynamic therapy, 120–121 CACD. See Central areolar choroidal dystrophy ranibizumab, 120–121 CACNA1F, congenital stationary night blindness nonneovascular disease, 118–119 mutations, 10 AGEs. See Advanced glycation end products CACNA2D4, congenital stationary night blindness AHI1, genetic modifiers, 62, 64 mutations, 10 AIPL1, Leber congenital amaurosis variants, 44 Candidate gene analysis ALMS1 age-related macular degeneration susceptibility Alstro¨m disease mutations, 101 studies, 157–158 inherited retinal degeneration, 46 genetic modifier identification, 62 Alstro¨m disease CAV1, glaucoma mutations, 211–212 clinical features, 101–102 CAV2, glaucoma mutations, 211–212 hearing loss, 100 CCDC28B, genetic modifiers, 57–58, 62, 65 AMD. See Age-related macular degeneration CCT. See Central corneal thickness Amyloid-b, drusen formation, 149 CDKN2BAS Angiostatin, gene therapy for age-related macular glaucoma mutations, 211–213, 215 degeneration, 314–315 therapeutic targeting, 255

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Central areolar choroidal dystrophy (CACD), molecular diagnosis, 277–278 clinical features, 104 REP1 Central corneal thickness (CCT), glaucoma, 195, 213 animal mutant studies, 279–280 CEP290 expression and function, 278–279 genetic modiﬁers, 56, 64 ChR2. See Channel rhodopsin-2 inherited retinal degeneration, 44, 46 Ciliary neurotrophic factor (CNTF) mouse model of Leber congenital amaurosis, 416 gene therapy, 356 mutation effects, 105–106 neuroprotection, 15, 255–256, 376 pathogenicity of mutations, 50 9-cis-Retinal, Retinal degeneration management retinitis pigmentosa mutations, 6–7 CLN1, neuronal ceroid lipofuscinosis mutation, CFB, age-related macular degeneration 103–104 susceptibility studies, 134 CLN3 CFD, age-related macular degeneration mutation effects, 106 susceptibility studies, 133 neuronal ceroid lipofuscinosis mutation, 104 CFG, age-related macular degeneration CLRN1, Usher syndrome mutations, 46 susceptibility studies, 133 CNGA1, retinitis pigmentosa mutations, 5 CFH CNGA3, achromatopsia mutations, 11, 46 age-related macular degeneration susceptibility CNGB3 studies, 129–134, 155–156, 159–161, achromatopsia mutations, 11 182–183 gene therapy, 13–14 drusen formation, 149–150 CNTF. See Ciliary neurotrophic factor genetic modiﬁers, 59 CNV. See Choroidal neovascularization; Copy induced pluripotent stem cell modeling number variation of mutation, 95 COL11A1, glaucoma mutations, 213 ligand lipoxidation in drusen, 148 COL15A1, genetic testing, 252 CFHR genes, age-related macular degeneration COL18A1, genetic testing, 252 susceptibility studies, 132 Color blindness CFI, age-related macular degeneration susceptibility developmental neural plasticity, 401 studies, 133, 135, 161 gene therapy prospects, 410–411 CFP, age-related macular degeneration susceptibility mouse trichromacy with M opsin knock-in, studies, 133 408–409 Channel rhodopsin-2 (ChR2), optogenetics, 16–17 squirrel monkey trichromacy CHM biological basis of trichromacy in primates, choroideremia mutations, 10, 42 406–408 gene therapy evolutionary mechanism of shift from clinical trials, 284–285 dichromacy, 405, 409 overview, 13, 275–277 gene therapy prospects, 285 delivery, 409–410 vector L opsin, 402–405 design, 280–283 neural networks in newly trichromatic preclinical testing of AAV2vector, 283–284 primates, 406 protein. See REP1 neural plasticity, 405–406 Choroidal neovascularization (CNV), age-related photopigments, 402 macular degeneration, 113–116 Complement Choroideremia activation pathways, 127 CHM gene therapy age-related macular degeneration clinical trials, 284–285 genome-wide association studies in overview, 13, 275–277 susceptibility prospects, 285 ARMS2, 129, 134 vector BF, 132 design, 280–283 C2, 132, 134 preclinical testing of AAV2vector, 283–284 C3, 133, 135 clinical features, 9–10 C5, 133 epidemiology, 277 C9, 135 gene mutations, 275–278 CFB, 134 history of study, 277 CFD, 133

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Complement (Continued) E CFG, 133 Eculizimab, age-related macular degeneration CFH, 129–134 management, 119 CFHR genes, 132 EFEMP1. See Extracellular matrix protein 1 CFI, 133, 135 EIAV. See Equine infectious anemia virus CFP, 133 Electroretinogram (ERG) genetic risk scores, 136–137 achromatopsia findings, 11 HTRA1, 129, 134 choroideremia findings, 10 meta-analysis of studies, 134–135 congenital stationary night blindness findings, 10 PLEKHA1, 129 Leber congenital amaurosis findings, 7 prospects, 135–136 retinitis pigmentosa findings, 2–3 highly penetrant alleles Stargardt disease findings, 8 C3, 158–159 X-linked retinoschisis findings, 8, 334–335 C9, 159 Embryonic stem cell (ESC) CFH, 155–156, 159–161 cell therapy, 17–18 CFI, 161 gene therapy, 416 glaucoma cascade, 238–239, 243–245 Endostatin, gene therapy for age-related macular Cone–rod degenerations/dystrophies (CORDs), degeneration, 314–315 overview, 7 ENDRA, genetic modifiers, 58 Congenital stationary night blindness (CSNB) ENDRB, genetic modifiers, 60 clinical features, 10 Equine infectious anemia virus (EIAV), gene gene mutations, 10 therapy vectors Copy number variation (CNV), inherited retinal endostatin delivery, 315 degeneration, 45–46 MYO7A delivery, 302–303 CORDs. See Cone–rod degenerations/dystrophies overview, 14 CRB1, Leber congenital amaurosis variants, 44 ERAP1, genetic modifiers, 70 CRISPR/Cas system, genome editing, 420–421 ERG. See Electroretinogram CRX ESC. See Embryonic stem cell Leber congenital amaurosis mutations, 7 EST. See Expressed sequence tags retinitis pigmentosa mutations, 5 Estrogen, metabolism and glaucoma, 215 CSNB. See Congenital stationary night blindness Exome chip analysis, age-related macular degeneration CYP1B1 susceptibility studies, 158 genetic testing, 250–252 Exome sequencing glaucoma expression, 222 age-related macular degeneration susceptibility glaucoma mutations, 208, 215 studies, 158 therapeutic targeting, 255 next generation sequencing, 44–45 Expressed sequence tags (EST), overview, 77 D Extracellular matrix protein 1 (EFEMP1), 144, 146, 149 DHA. See Docosahexaenoic acid DNA microarrays, age-related macular F degeneration gene expression FAM161A, variant prioritization, 49 studies, 174–176 Fanconi anemia, gene therapy, 418 Docosahexaenoic acid (DHA), retinal degeneration FBLN5, age-related macular degeneration management, 11 susceptibility studies, 162 Drusen FCD. See Fuchs corneal dystrophy clinical features, 112, 141 FECH, genetic modifiers, 58 formation, 142, 149 FGF. See Fibroblast growth factor proteomics studies in age-related macular Fibroblast growth factor (FGF), FGF-2 degeneration neuroprotection, 15 oxidative protein modifications, 146–149 Fluorescein angiography, choroidal prospects, 149–150 neovascularization, 114 qualitative studies, 142–143 FOXC1 quantitative studies genetic testing, 250–252, 254 Bruch’s membrane/choroid, 143–145 glaucoma mutations, 209 mouse studies, 144, 146 FTO, genetic modifiers, 58

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Fuchs corneal dystrophy (FCD), genetic modifiers, 60 overview, 211–212 Fundus autofluorescence primary open-angle glaucoma, 213 retinitis pigmentosa findings, 2–3 pseudoexfoliation syndrome, 212–213 Stargardt disease findings, 8–9 qualitative ocular traits as risk factors, 213 complex interactions, 213–214 early-onset disease G congenital glaucoma, 208–209 Gene therapy. See also specific diseases and genes developmental glaucoma, 209 economic considerations, 432–433 juvenile-onset primary open-angle efficacy improvement, 429–431 glaucoma, 209–211 indications, 12–14 normal-tension glaucoma, 211 limitations, 431–432 overview, 207–208 outcome measures, 432 estrogen metabolism, 215 prospects, 433 extracellular matrix metabolism, 215 success stories, 427–429 gene discovery rationale, 207 vectors, 12–13 prospects for study, 215 Genetic modifiers transforming growth factor-b signaling, 215 cloning strategies tumor necrosis factor-a signaling, 215 candidate gene approach, 62 genetic testing candidate locus association studies, 60, 62 adult-onset glaucoma, 262 linkage analysis, 60 approaches, 254 mouse strain studies, 63–64 early-onset glaucoma overview, 60–61 gene mutations, 250 system-based candidates, 62 informed genetic counseling, 250–251 transcriptome analysis, 62–63 presymptomatic risk assessment, 251 whole-exome data in toto, 63 surveillance and treatment plans, 251–252 identification challenges limitations, 254 nongenetic factors, 59–60 overview, 250 study availability, 59 recommendations, 252 overview, 55–56 history taking, 193–194 properties natural history, 191–192 allelic heterogeneity, 56 neuroinflammation and retinal ganglion cell loss locus sharing with disease driver, 58 astrocyte and microglia activation, 239–240 multiple interactions, 56–58 beneficial and damaging effects, 239 variant frequency in general population, 58–59 complement cascade, 238–239, 243–245 prospects for study, 70–71 immune response, 236 retinal degeneration studies inflammation signaling, 240–242 humans, 64–65, 67–68 leukocyte transendothelial migration, 238, mice, 66, 68–70 242–243 Genome editing, induced pluripotent stem cells, overview, 235–236 419–421 triggers, 236–238, 240 Geographic atrophy, age-related macular novel therapy identification, 254–256 degeneration, 112–114 ophthalmic examination, 194–198 GFAP. See Glial fibrillary acidic protein treatment Glaucoma clinical trials, 203–204 etiology, 192–193 laser therapy, 202 gene expression studies medical therapy, 200–202 anterior eye, 222 overview, 197, 200 ganglion cell central projecting targets, 228 surgery, 202, 204 optic nerve, 225–228 types, 192 overview, 221–222 Glial fibrillary acidic protein (GFAP), glaucoma prospects for study, 228–229 expression, 225, 228 retina, 222–225 Glutathione S-transferase (GST), expression in age- genetics related macular degeneration, 174 adult-onset glaucoma GNAT2, achromatopsia mutations, 11 normal-tension glaucoma, 212 Gonioscopy, glaucoma, 194–195

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GPR179, congenital stationary night blindness vectors, 417–418 mutations, 10 generation, 417 GRM6, congenital stationary night blindness photoreceptor cell differentiation, 416–417 mutations, 10 retinal disease modeling GST. See Glutathione S-transferase ABCA4 diseases, 92–93 Guanylate cyclase. See GUCY2D age-related macular degeneration, 94–95 GUCY2D BEST1 mutation, 94 gene therapy prospects, 327–328 MAK mutation, 93 Leber congenital amaurosis mutations overview, 92 animal models prospects, 95–96 GC1/GC2 double knockout mouse, USH2A mutation, 93–94 325–327 RNA-Seq studies, 83 GUCY1ÃB chicken, 321–323 iPSC. See Induced pluripotent stem cell knockout mouse, 323–325 IQCB1 guanylate cyclase functions, 319–320 genetic modifiers, 65 patient characterization, 320–321 inherited retinal degeneration, 46 GUCY2D, Leber congenital amaurosis variants, 44 IRX3, genetic modifiers, 58 Gyrate atrophy, OAT mutation, 42, 104 J H Joubert syndrome Hirschsprung disease, genetic modifiers, 58 gene mutations, 46 HIV. See Human immunodeficiency virus retinitis pigmentosa, 6–7 HK1, retinitis pigmentosa mutations, 35, 106 HMCN1 age-related macular degeneration susceptibility L studies, 163 Latanoprost, glaucoma management, 201 variant prioritization, 49 LCA. See Leber congenital amaurosis HTRA1 Leber congenital amaurosis (LCA) age-related macular degeneration susceptibility animal models of RPGRIP1 mutation, 365–367 studies, 129, 134, 155–156 clinical features, 7–8, 363 expression in age-related macular degeneration, 172 epidemiology, 7 induced pluripotent stem cell modeling of gene therapy mutation, 95 genes. See RPE65; RPGRIP1 Human immunodeficiency virus (HIV), gene therapy overview, 12–13 vector for MYO7A delivery, 302 GUCY2D mutations animal models GC1/GC2 double knockout mouse, 325–327 I GUCY1ÃB chicken, 321–323 IBD. See Identity by descent knockout mouse, 323–325 Identity by descent (IBD), mapping, 45 gene therapy prospects, 327–328 IFRD1, genetic modifiers, 58 guanylate cyclase functions, 319–320 IMPDH1 patient characterization, 320–321 Leber congenital amaurosis mutations, 7 Leber’s hereditary optic neuropathy. See Primary retinitis pigmentosa mutations, 34–35 optic neuropathy Indocyanine green angiopathy, polyploidal choroidal Lentivirus gene therapy vectors. See also specific viruses vasculopathy, 117 ABCA4 delivery, 293–294 Induced pluripotent stem cell (iPSC) MYO7A delivery, 302–303 cell therapy, 17–18, 91 Leukocyte transendothelial migration, glaucoma, 238, differentiation, 92 242–243 gene therapy Linkage analysis Fanconi anemia, 418 age-related macular degeneration susceptibility genome editing, 419–421 studies, 157 promoters, 419 genetic modifier identification, 60 prospects, 421–422 inherited retinal degeneration, 45–46 timing, 418 LMX1B, glaucoma mutations, 209

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L opsin, gene therapy in dichromatic primates, 402–405 NOD-like receptors, glaucoma LOXL1 neuroinflammation role, 237 genetic testing, 252 Normal-tension glaucoma. See Glaucoma glaucoma mutations, 213 NPHP1, genetic modifiers, 62 LRIT3, congenital stationary night blindness NR2E3, retinitis pigmentosa mutations, 5 mutations, 10 NRL, retinitis pigmentosa mutations, 5 LTBP2 NYX, congenital stationary night blindness genetic testing, 250–252 mutations, 10 glaucoma mutations, 208–209, 215 Lutein age-related macular degeneration management, 118 O retinal degeneration management, 11 OAT, gyrate atrophy mutation, 42, 104 OCT. See Optical coherence tomography OFD1, Joubert syndrome mutations, 46 M OPA1, genetic testing, 252–254 MAK OPA3, genetic testing, 252–254 induced pluripotent stem cell modeling Optic nerve disorders. See Glaucoma; Primary optic of mutation, 93 neuropathy variant prioritization, 49 Optical coherence tomography (OCT) MBL2, genetic modifiers, 58 achromatopsia findings, 11 MELAS, pigmentary retinopathy, 102 choroidal neovascularization, 115–116 MERTK, gene therapy, 13 congenital stationary night blindness findings, 10 MFSD8, mutation effects, 106 gene therapy studies, 430 Mitochondrial disease, pigmentary retinopathy, 102 glaucoma, 197–198 Mtap1a, genetic modifiers, 66 patient selection for retinal degeneration MTTP, Bassen–Kornzweig syndrome mutation, 103 treatment, 18 MVK, retinitis pigmentosa mutations, 46 reticular pseudodrusen, 112 MYO7A retinitis pigmentosa findings, 2–3 gene therapy Stargardt disease findings, 8 adeno-associated virus vectors X-linked retinoschisis, 335 dual vectors, 304–305 OPTN single vectors, 303–304 genetic testing, 250–252 equine infectious anemia virus vectors, 302–303 glaucoma mutations, 211, 215 human immunodeficiency virus vectors, 302 Optogenetics, vision restoration, 16–17 prospects, 306, 429 OTUD4, genetic modifiers, 63 splice variants, 305–306 OTX2, Leber congenital amaurosis mutations, 7 inherited retinal degeneration, 46 mouse mutants, 299–302 MYOC P genetic testing, 250–252 Palmitoyl protein thioesterase (PPT), neuronal glaucoma mutations, 210, 215 ceroid lipofuscinosis role, 103 therapeutic targeting, 255 PAX6 genetic testing, 250–252 glaucoma mutations, 209 N PCV. See Polyploidal choroidal vasculopathy Neuronal ceroid lipofuscinosis, clinical features and PDE-b, retinitis pigmentosa mutations, 5 gene mutations, 103–104 PDE6A, retinitis pigmentosa mutations, 5 Next generation sequencing (NGS). See also RNA-Seq PDE6B, retinitis pigmentosa mutations, 5 autosomal dominant retinitis pigmentosa genetic PDE6C, achromatopsia mutations, 11 testing, 28, 30–31, 36 PDE6H, achromatopsia mutations, 11 clinical applications in ophthalmology, 78–79 PDT. See Photodynamic therapy exome sequencing, 44–45 PDZD7, genetic modifiers, 65 overview, 78 PED. See Retinal pigment epithelial detachment targeted sequencing, 44 PEDF. See Pigment epithelium-derived factor NGS. See Next generation sequencing Pegaptanib, age-related macular degeneration Nilvadipine, retinal degeneration management, 16 management, 120

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Peripherin-2. See PRPH2 R PEX7, Refsum disease mutation, 102 Ranibizumab, age-related macular degeneration man- Photocoagulation, age-related macular degeneration agement, 120–121 management, 119 RAP. See Retinal angiomatous proliferation Photodynamic therapy (PDT), age-related macular RdCVF. See Rod-derived cone viability factor degeneration management, 120–121 RDH12, retinitis pigmentosa mutations, 28 PHYH, Refsum disease mutation, 102 RDS, genetic modifiers, 64 Pigment epithelium-derived factor (PEDF), gene therapy Refsum disease age-related macular degeneration, 313–314 clinical features, 102 neuroprotection, 15 hearing loss, 100 PRPH2 diseases, 356 REP1 PITX2 animal mutant studies, 279–280 genetic testing, 250–252 expression and function, 278–279 glaucoma mutations, 209 functional overview, 10 PLEKHA1, age-related macular degeneration gene. See CHM susceptibility studies, 129 RET, genetic modifiers, 60, 62 PLINK, single nucleotide polymorphism analysis, 45 Reticular pseudodrusen. See Drusen PLS3, genetic modifiers, 63 Retina, structure, 90 Polyploidal choroidal vasculopathy (PCV), age-related Retinal angiomatous proliferation (RAP), age-related macular degeneration, 116–117 macular degeneration, 117 PPT. See Palmitoyl protein thioesterase Retinal pigment epithelial detachment (PED), choroidal Primary open-angle glaucoma. See Glaucoma neovascularization, 114–115 Primary optic neuropathy Retinal pigment epithelium (RPE), hyperplasia, 116 genetic testing Retinitis pigmentosa (RP) approaches, 254 autosomal dominant disease gene mutations. See gene mutations, 252–253 also PRPH2; RHO gene therapy candidate identification, 253 discovery, 28, 30–31 informed genetic counseling, 253 dominant-recessive acting mutations, 35 limitations, 254 genetic testing, 28, 30–31, 36 risk assessment, 253 overview, 27–28 novel therapy identification, 254–256 pathogenicity, 31–32 risk factor avoidance, 253 prevalence of mutations, 32–35 PRPF3, retinitis pigmentosa mutations, 35 protein functions, 35 PRPF31, retinitis pigmentosa mutations, 30–33, 35 reconciling diagnosis, family history, and PRPF4, retinitis pigmentosa mutations, 35 molecular findings, 35–36 PRPF6, retinitis pigmentosa mutations, 35 table, 29–30 PRPF8, retinitis pigmentosa mutations, 35 classification, 1–2 PRPH2 clinical features, 2–3, 27 animal models of mutations, 349–351 epidemiology, 3–4, 27 autosomal-dominant retinitis pigmentosa gene therapy. See PRPH2; RHO mutations, 348–349 genetics, 4–5 central areolar choroidal dystrophy mutations, 104 syndromic/systemic forms, 5–7 functional overview, 347–348 treatment gene therapy alternative pharmacotherapy, 15–16 adeno-associated virus vectors, 352–353 cell therapy, 17–18 knockdown therapy, 355 neuroprotection, 15 neuroprotection, 355–356 overview, 11 plasmid DNA vectors, 353–355 retinal prosthetics, 16 prospects, 357 Retinoschisin. See RS1 transgene replacement, 351–352 RHO vascular endothelial growth factor inhibitors, gene therapy 356–357 adeno-associated virus specificity, 389 genetic modifiers, 61–62 clinical prospects, 395–396 retinitis pigmentosa mutations, 5, 31, 33, 35 expression levels, 389–390 Pseudoexfoliation syndrome. See Glaucoma photoreceptor rescue, 390–392

444

RHO (Continued) prospects, 383 rationale, 388–389 vectors, 376 RNA replacement, 392–395 mutations and phenotypes, 371–373 vectors, 389 neuroprotection studies, 376 zinc-finger repressors, 392 RPGRIP1 genomics studies, 43 animal models of mutation, 365–367 retinitis pigmentosa mutations, 4–5, 31, 55, functional overview, 364–365 387–388 gene therapy prospects, 367–368 RNA-Seq Leber congenital amaurosis mutations, 363 age-related macular degeneration gene expression RPGRIP1L, genetic modifiers, 59, 64–65 studies, 174–176 RPIL1, variant prioritization, 49 bioinformatics RS1 alignment of data, 80 developmental expression, 336 differential expression analysis, 80–82 functional overview, 335 inherited retinal disease models, 82–83 gene therapy mechanisms, 83–84 administration route, 339, 341 next generation library preparation, 79–80 efficacy, 341–343 overview, 78–79 overview, 14 retina transcripts, 82 prospects, 343 RNF216, genetic modifiers, 63 vectors, 337–339 Rod-derived cone viability factor (RdCVF), 15 mouse mutants, 336–337, 340 ROM1 X-linked retinoschisis mutations, 8, 335–336 genetic modifiers, 61–62, 64 retinitis pigmentosa mutations, 5, 33 RP. See Retinitis pigmentosa S RP1, retinitis pigmentosa mutations, 5, 35 SAA. See Serum Amyloid A RP2, retinitis pigmentosa mutations, 32, 34 SAG, retinitis pigmentosa mutations, 5 RPE. See Retinal pigment epithelium SAGE. See Serial analysis of gene expression RPE65 SCA. See Spinocerebellar ataxia functional overview, 260–261 Senior–Løken syndrome gene therapy gene mutations, 46 animal models, 415 retinitis pigmentosa, 5 clinical trials Serial analysis of gene expression (SAGE), outcome measures, 268 overview, 77 Phase I/II trials, 260, 263–265 Serum Amyloid A (SAA), glaucoma Phase II, 265 expression, 224 Phase III, 265 sFLT01, gene therapy for age-related macular table, 261–262 degeneration, 311–312 overview, 259–260, 427–428, 430–431 SIX1, glaucoma mutations, 211–213 prevention of retina degradation, 266–267 SIX6, glaucoma mutations, 211–213 prospects, 269–270 SMA. See Spinal muscle atrophy subretinal injection safety, 267–268 Spinal muscle atrophy (SMA), genetic modifiers, 63 genetic modifiers, 68 Spinocerebellar ataxia (SCA), genetic modifiers retinitis pigmentosa mutations, 28 in SCA1, 62 RPGR Stargardt disease functional overview, 372 ABCA4 mutations, 9, 42, 289 mutation effects, 105 clinical features, 8–9 retinitis pigmentosa mutations, 32–35 gene therapy. See ABCA4 X-linked retinoschisis STAT3, glaucoma expression, 224 animal models dog, 373–376 mouse, 373 T gene therapy TALENs, genome editing, 420–421 dog studies, 376–383 TBK1 onset prevention, 377 genetic testing, 250–252 photoreceptor rescue, 377–383 glaucoma mutations, 211, 215

445

TCF8, genetic modifiers, 60 V TGF-b. See Transforming growth factor-b Valproic acid, retinal degeneration Timolol, glaucoma management, 201 management, 15 TLRs. See Toll-like receptors Vascular endothelial growth factor (VEGF) TNF-a. See Tumor necrosis factor-a inhibitor gene therapy Toll-like receptors (TLRs), glaucoma neuroinflamma- age-related macular degeneration, 310–312 tion role, 236–237, 240–241 PRPH2 diseases, 356–357 Trabeculectomy, glaucoma management, 202, 204 inhibitor therapy for age-related macular Trabeculoplasty, glaucoma management, 202 degeneration, 120–121 Transcriptomics. See also RNA-Seq VEGF. See Vascular endothelial growth factor genetic modifier identification, 62–63 Vitamin A, retinal degeneration management, 11 inherited retinal degeneration, 47 Transforming growth factor-b (TGF-b) glaucoma expression, 222, 227, 229 W signaling and glaucoma, 215 Whole genome sequencing Travoprost, glaucoma management, 201 age-related macular degeneration susceptibility TRPM1, congenital stationary night blindness studies, 158 mutations, 10 inherited retinal degeneration, 47 TSPAN12, linkage studies, 45 Tumor necrosis factor-a (TNF-a) glaucoma expression, 225, 228–229 X signaling and glaucoma, 215, 241 X-linked retinoschisis (XLRS) clinical features, 8, 333–335 epidemiology, 8 U gene and cell biology, 335, 371 USH2A, induced pluripotent stem cell modeling gene therapy. See RPGR; RS1 of mutation, 93–94 genetic modifiers, 68 Usher syndrome management, 335 gene mutations, 46 mouse models, 336–337, 340 genetic modifiers, 65 XLPR dog models. See RPGR hearing loss, 100–101 XLRS. See X-linked retinoschisis mouse models, 299–302 MYO7A gene therapy. See MYO7A retinitis pigmentosa, 5–6 Z types, 100 ZNF408, linkage studies, 45

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