Splicing mutations in inherited retinal diseases

Progress in Retinal and Eye Research - Tập 80 - Trang 100874 - 2021
Nicole Weisschuh1, Elena Buena-Atienza1, Bernd Wissinger1
1Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Germany

Tài liệu tham khảo

Abramowicz, 2018, Splicing mutations in human genetic disorders: examples, detection, and confirmation, J. Appl. Genet., 59, 253, 10.1007/s13353-018-0444-7 Adamson, 2018, Vex-seq: high-throughput identification of the impact of genetic variation on pre-mRNA splicing efficiency, Genome Biol., 19, 71, 10.1186/s13059-018-1437-x Albert, 2018, Identification and rescue of splice defects caused by two neighboring deep-intronic ABCA4 mutations underlying Stargardt disease, Am. J. Hum. Genet., 102, 517, 10.1016/j.ajhg.2018.02.008 Alter, 2006, Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology, Nat. Med. 12, 175, 10.1038/nm1345 Aparisi, 2013, Study of USH1 splicing variants through minigenes and transcript analysis from nasal epithelial cells, PloS One, 8, 10.1371/journal.pone.0057506 Aukrust, 2017, The intronic ABCA4 c.5461-10T>C variant, frequently seen in patients with Stargardt disease, causes splice defects and reduced ABCA4 protein level, Acta Ophthalmol., 95, 240, 10.1111/aos.13273 Bacchi, 2014, Splicing-correcting therapeutic approaches for retinal dystrophies: where endogenous gene regulation and specificity matter, Invest. Ophthalmol. Vis. Sci., 55, 3285, 10.1167/iovs.14-14544 Baden, 2016, The functional diversity of retinal ganglion cells in the mouse, Nature, 529, 345, 10.1038/nature16468 Balestra, 2014, An engineered U1 small nuclear RNA rescues splicing defective coagulation F7 gene expression in mice, J. Thromb. Haemostasis, 12, 177, 10.1111/jth.12471 Baralle, 2017, Alternative splicing as a regulator of development and tissue identity, Nat. Rev. Mol. Cell Biol., 18, 437, 10.1038/nrm.2017.27 Baranello, 2019, FIREFISH Part 1: 1–year results on motor function in babies with type 1 SMA, Annu. Meet. Am. Acad. Neurol., 92 Barny, 2019 Bauwens, 2019, ABCA4-associated disease as a model for missing heritability in autosomal recessive disorders: novel noncoding splice, cis-regulatory, structural, and recurrent hypomorphic variants, Genet Med, 10.1038/s41436-018-0420-y Bax, 2015, Heterozygous deep-intronic variants and deletions in ABCA4 in persons with retinal dystrophies and one exonic ABCA4 variant, Hum. Mutat., 36, 43, 10.1002/humu.22717 Becirovic, 2008, Usher syndrome type 1 due to missense mutations on both CDH23 alleles: investigation of mRNA splicing, Hum. Mutat., 29, 452, 10.1002/humu.9526 Becirovic, 2016, Vivo analysis of disease-associated point mutations unveils profound differences in mRNA splicing of peripherin-2 in rod and cone photoreceptors, PLoS Genet., 12, 10.1371/journal.pgen.1005811 Berger, 2010, The molecular basis of human retinal and vitreoretinal diseases, Prog. Retin. Eye Res., 29, 335, 10.1016/j.preteyeres.2010.03.004 Berger, 2015, Repair of rhodopsin mRNA by spliceosome-mediated RNA trans-splicing: a new approach for autosomal dominant retinitis pigmentosa, Mol. Ther., 23, 918, 10.1038/mt.2015.11 Berger, 2016, mRNA trans-splicing in gene therapy for genetic diseases, Wiley. Interdis. Rev. RNA, 7, 487, 10.1002/wrna.1347 Black, 2003, Mechanisms of alternative pre-messenger RNA splicing, Annu. Rev. Biochem., 72, 291, 10.1146/annurev.biochem.72.121801.161720 Blencowe, 2000, Exonic splicing enhancers: mechanism of action, diversity and role in human genetic diseases, Trends Biochem. Sci., 25, 106, 10.1016/S0968-0004(00)01549-8 Bok, 1972, The renewal of diffusely distributed protein in the outer segments of rods and cones, Vis. Res., 12, 161, 10.1016/0042-6989(72)90108-3 Bonifert, 2016, Antisense oligonucleotide mediated splice correction of a deep intronic mutation in OPA1, Mol. Ther. Nucleic Acids, 5, e390, 10.1038/mtna.2016.93 Bonifert, 2014, 137, 2164 Braun, 2013, Non-exomic and synonymous variants in ABCA4 are an important cause of Stargardt disease, Hum. Mol. Genet., 22, 5136, 10.1093/hmg/ddt367 Broadgate, 2017, Unravelling the genetics of inherited retinal dystrophies: past, present and future, Prog. Retin. Eye Res., 59, 53, 10.1016/j.preteyeres.2017.03.003 Bronstein, 2020, A combined RNA-seq and whole genome sequencing approach for identification of non-coding pathogenic variants in single families, Hum. Mol. Genet., 29, 967, 10.1093/hmg/ddaa016 Buckler, 1991, Exon amplification: a strategy to isolate mammalian genes based on RNA splicing, Proc. Natl. Acad. Sci. U.S.A., 88, 4005, 10.1073/pnas.88.9.4005 Buena-Atienza, 2016, De novo intrachromosomal gene conversion from OPN1MW to OPN1LW in the male germline results in Blue Cone Monochromacy, Sci. Rep., 6, 28253, 10.1038/srep28253 Burnight, 2018, CRISPR-Cas9 genome engineering: treating inherited retinal degeneration, Prog. Retin. Eye Res., 65, 28, 10.1016/j.preteyeres.2018.03.003 Burset, 2000, Analysis of canonical and non-canonical splice sites in mammalian genomes, Nucleic Acids Res., 28, 4364, 10.1093/nar/28.21.4364 Buskin, 2018, Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa, Nat. Commun., 9, 4234, 10.1038/s41467-018-06448-y Busslinger, 1981, Beta + thalassemia: aberrant splicing results from a single point mutation in an intron, Cell, 27, 289, 10.1016/0092-8674(81)90412-8 Cáceres, 1994, Regulation of alternative splicing in vivo by overexpression of antagonistic splicing factors, Science, 265, 1706, 10.1126/science.8085156 Carss, 2017, Comprehensive rare variant analysis via whole-genome sequencing to determine the molecular pathology of inherited retinal disease, Am. J. Hum. Genet., 100, 75, 10.1016/j.ajhg.2016.12.003 Cartegni, 2002, Listening to silence and understanding nonsense: exonic mutations that affect splicing, Nat. Rev. Genet., 3, 285, 10.1038/nrg775 Chaitankar, 2016, Next generation sequencing technology and genomewide data analysis: perspectives for retinal research, Prog. Retin. Eye Res., 55, 1, 10.1016/j.preteyeres.2016.06.001 Chang, 2009, A homologous genetic basis of the murine cpfl1 mutant and human achromatopsia linked to mutations in the PDE6C gene, Proc. Natl. Acad. Sci. U. S. A., 106, 19581, 10.1073/pnas.0907720106 Chao, 2003, Phenotype correction of hemophilia A mice by spliceosome-mediated RNA trans-splicing, Nat. Med., 9, 1015, 10.1038/nm900 Chen, 2014, Correcting for differential transcript coverage reveals a strong relationship between alternative splicing and organism complexity, Mol. Biol. Evol., 31, 1402, 10.1093/molbev/msu083 Cideciyan, 2019, Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect, Nat. Med., 25, 225, 10.1038/s41591-018-0295-0 Cirak, 2011, Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study, Lancet, 378, 595, 10.1016/S0140-6736(11)60756-3 Cremers, 2020, Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations. Prog Retin Eye Res, Apr, 9 Crognale, 2004, Characterization of a novel form of X-linked incomplete achromatopsia, Vis. Neurosci., 21, 197, 10.1017/S0952523804213384 da Palma, 2020, Synonymous variant in the CHM gene causes aberrant splicing in choroideremia, Invest. Ophthalmol. Vis. Sci., 61, 38, 10.1167/iovs.61.2.38 Davidson, 2010, A synonymous codon variant in two patients with autosomal recessive bestrophinopathy alters in vitro splicing of BEST1, Mol. Vis., 16, 2916 den Hollander, 2006, Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis, Am. J. Hum. Genet., 79, 556, 10.1086/507318 Desmet, 2009, Human Splicing Finder: an online bioinformatics tool to predict splicing signals, Nucleic Acids Res., 37, e67, 10.1093/nar/gkp215 Desviat, 2012, Minigenes to confirm exon skipping mutations, vol. 867 Dhir, 2010, Alternative splicing: role of pseudoexons in human disease and potential therapeutic strategies, FEBS J., 277, 841, 10.1111/j.1742-4658.2009.07520.x Dias, 2018, Molecular genetics and emerging therapies for retinitis pigmentosa: basic research and clinical perspectives, Prog. Retin. Eye Res., 63, 107, 10.1016/j.preteyeres.2017.10.004 Donadon, 2018, Exon-specific U1 snRNAs improve ELP1 exon 20 definition and rescue ELP1 protein expression in a familial dysautonomia mouse model, Hum. Mol. Genet., 27, 2466, 10.1093/hmg/ddy151 Dooley, 2018, Spliceosome-mediated pre-mRNA trans-splicing can repair CEP290 mRNA, Mol. Ther. Nucleic Acids, 12, 294, 10.1016/j.omtn.2018.05.014 Dulla, 2018, Splice-modulating oligonucleotide QR-110 restores CEP290 mRNA and function in human c.2991+1655A>G LCA10 models, Mol. Ther. Nucleic Acids, 12, 730, 10.1016/j.omtn.2018.07.010 Erkelenz, 2014, Genomic HEXploring allows landscaping of novel potential splicing regulatory elements, Nucleic Acids Res., 42, 10681, 10.1093/nar/gku736 Fairbrother, 2004, RESCUE-ESE identifies candidate exonic splicing enhancers in vertebrate exons, Nucleic Acids Res., 32, 187, 10.1093/nar/gkh393 Farkas, 2013, Transcriptome analyses of the human retina identify unprecedented transcript diversity and 3.5 Mb of novel transcribed sequence via significant alternative splicing and novel genes, BMC Genom., 14, 486, 10.1186/1471-2164-14-486 Franke, 2017, Inhibition decorrelates visual feature representations in the inner retina, Nature, 542, 439, 10.1038/nature21394 Frischmeyer, 1999, Nonsense-mediated mRNA decay in health and disease, Hum. Mol. Genet., 8, 1893, 10.1093/hmg/8.10.1893 Gao, 2008, Human branch point consensus sequence is yUnAy, Nucleic Acids Res., 36, 2257, 10.1093/nar/gkn073 Garafalo, 2019, Progress in treating inherited retinal diseases: early subretinal gene therapy clinical trials and candidates for future initiatives, Prog. Retin. Eye Res. Garanto, 2013, Unexpected CEP290 mRNA splicing in a humanized knock-in mouse model for leber congenital amaurosis, PloS One, 8, 10.1371/journal.pone.0079369 Garanto, 2016, In vitro and in vivo rescue of aberrant splicing in CEP290-associated LCA by antisense oligonucleotide delivery, Hum. Mol. Genet., 25, 2552 Garanto, 2018, Antisense oligonucleotide-based splice correction of a deep-intronic mutation in CHM underlying choroideremia, Adv. Exp. Med. Biol., 1074, 83, 10.1007/978-3-319-75402-4_11 Gardner, 2014, Three different cone opsin gene array mutational mechanisms with genotype-phenotype correlation and functional investigation of cone opsin variants, Hum. Mutat., 35, 1354 Gerard, 2012, AON-mediated exon skipping restores ciliation in fibroblasts harboring the common leber congenital amaurosis CEP290 mutation, Mol. Ther. Nucleic Acids, 1, e29, 10.1038/mtna.2012.21 Gérard, 2015, Intravitreal injection of splice-switching oligonucleotides to manipulate splicing in retinal cells, Mol. Ther. Nucleic Acids, 4, e250, 10.1038/mtna.2015.24 Gilbert, 1978, Why genes in pieces?, Nature, 271, 501, 10.1038/271501a0 Glaus, 2011, Gene therapeutic approach using mutation-adapted U1 snRNA to correct a RPGR splice defect in patient-derived cells, Mol. Ther., 19, 936, 10.1038/mt.2011.7 Goemans, 2011, Systemic administration of PRO051 in Duchenne's muscular dystrophy, N. Engl. J. Med., 364, 1513, 10.1056/NEJMoa1011367 Goemans, 2016, Long-Term Efficacy, Safety, and Pharmacokinetics of Drisapersen in Duchenne Muscular Dystrophy: results from an Open-Label Extension Study, PLoS One, 11, 10.1371/journal.pone.0161955 Gonorazky, 2019, Expanding the boundaries of RNA sequencing as a diagnostic tool for rare mendelian disease, Am. J. Hum. Genet., 104, 1007, 10.1016/j.ajhg.2019.04.004 Greenwald, 2017, Role of a dual splicing and amino acid code in myopia, cone dysfunction and cone dystrophy associated with L/M opsin interchange mutations, Transl. Vis. Sci. Technol., 6, 2, 10.1167/tvst.6.3.2 Grodecká, 2017, Mutations of pre-mRNA splicing regulatory elements: are predictions moving forward to clinical diagnostics?, Int. J. Mol. Sci., 18, 1668, 10.3390/ijms18081668 Grünert, 2020, Cell types and cell circuits in human and non-human primate retina, Prog. Retin. Eye. Res. Feb., 5, 100844, 10.1016/j.preteyeres.2020.100844 GTEx Consortium, 2017, Genetic effects on gene expression across human tissues, Nature, 550, 204, 10.1038/nature24277 Gu, 1997, Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy, Nat. Genet., 17, 194, 10.1038/ng1097-194 Hong, 2002, Complex expression pattern of RPGR reveals a role for purine-rich exonic splicing enhancers, Invest. Ophthalmol. Vis. Sci., 43, 3373 Hoon, 2014, Functional architecture of the retina: development and disease, Prog. Retin. Eye Res., 42, 44, 10.1016/j.preteyeres.2014.06.003 Hubé, 2015, Mammalian introns: when the junk generates molecular diversity, Int. J. Mol. Sci., 16, 4429, 10.3390/ijms16034429 Huelga, 2012, Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins, Cell Rep., 1, 167, 10.1016/j.celrep.2012.02.001 Irimia, 2014, A highly conserved program of neuronal microexons is misregulated in autistic brains, Cell, 159, 1511, 10.1016/j.cell.2014.11.035 Jaganathan, 2019, Predicting splicing from primary sequence with deep learning, Cell, 176, 535, 10.1016/j.cell.2018.12.015 Jamshidi, 2019, Contribution of noncoding pathogenic variants to RPGRIP1-mediated inherited retinal degeneration, Genet. Med., 21, 694, 10.1038/s41436-018-0104-7 Jian, 2014, In silico tools for splicing defect prediction: a survey from the viewpoint of end users, Genet. Med., 16, 497, 10.1038/gim.2013.176 Johnson, 2017, Bestrophin 1 and retinal disease, Prog. Retin. Eye Res., 58, 45, 10.1016/j.preteyeres.2017.01.006 Kapustin, 2011, Cryptic splice sites and split genes, Nucleic Acids Res., 39, 5837, 10.1093/nar/gkr203 Katz, 2013 Ke, 2011, Quantitative evaluation of all hexamers as exonic splicing elements, Genome Res., 21, 1360, 10.1101/gr.119628.110 Khan, 2017, A deep intronic CLRN1 (USH3A) founder mutation generates an aberrant exon and underlies severe Usher syndrome on the Arabian Peninsula, Sci. Rep., 7, 1411, 10.1038/s41598-017-01577-8 Khan, 2019, Identification and analysis of genes associated with inherited retinal diseases, Methods Mol. Biol., 1834, 3, 10.1007/978-1-4939-8669-9_1 Kim, 2008, Alternative splicing: current perspectives, Bioessays, 30, 38, 10.1002/bies.20692 Kim, 2016, NRL-regulated transcriptome dynamics of developing rod photoreceptors, Cell Rep., 17, 2460, 10.1016/j.celrep.2016.10.074 Kloeckener-Gruissem, 1993, VCAN-related vitreoretinopathy Kohl, 2015, Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia, Nat. Genet., 47, 757, 10.1038/ng.3319 Krausová, 2018, snRNP proteins in health and disease, Semin. Cell Dev. Biol., 79, 92, 10.1016/j.semcdb.2017.10.011 Krawczak, 1992, The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences, Hum. Genet., 90, 41, 10.1007/BF00210743 Krawczak, 2007, Single base-pair substitutions in exon-intron junctions of human genes: nature, distribution, and consequences for mRNA splicing, Hum. Mutat., 28, 150, 10.1002/humu.20400 Kuivenhoven, 1996, An intronic mutation in a lariat branchpoint sequence is a direct cause of an inherited human disorder (fish-eye disease), J. Clin. Invest., 98, 358, 10.1172/JCI118800 Lee, 2016, Mutation-adapted U1 snRNA corrects a splicing error of the dopa decarboxylase gene, Hum. Mol. Genet., 25, 5142 Lee, 2017, Systematic computational identification of variants that activate exonic and intronic cryptic splice sites, Am. J. Hum. Genet., 100, 751, 10.1016/j.ajhg.2017.04.001 Lee, 2019, Gene therapy for visual loss: opportunities and concerns, Prog. Retin. Eye Res., 68, 31, 10.1016/j.preteyeres.2018.08.003 Lei, 2016, Evolutionary insights into RNA trans-splicing in vertebrates, Genome Biol. Evol., 8, 562, 10.1093/gbe/evw025 Lenassi, 2014, The effect of the common c.2299delG mutation in USH2A on RNA splicing, Exp. Eye Res., 122, 9, 10.1016/j.exer.2014.02.018 Lentz, 2013, Rescue of hearing and vestibular function by antisense oligonucleotides in a mouse model of human deafness, Nat. Med., 19, 345, 10.1038/nm.3106 Li, 2019, Aberrant RNA splicing is the major pathogenic effect in a knock-in mouse model of the dominantly inherited c.1430A>G human RPE65 mutation, Hum. Mutat., 40, 426, 10.1002/humu.23706 Liang, 2019, Single-nuclei RNA-seq on human retinal tissue provides improved transcriptome profiling, Nat. Commun., 10, 5743, 10.1038/s41467-019-12917-9 Lim, 2011, Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes, Proc. Natl. Acad. Sci. U. S. A., 108, 11093, 10.1073/pnas.1101135108 Liquori, 2016, Whole USH2A gene sequencing identifies several new deep intronic mutations, Hum. Mutat., 37, 184, 10.1002/humu.22926 Liu, 2002, Partial correction of endogenous DeltaF508 CFTR in human cystic fibrosis airway epithelia by spliceosome-mediated RNA trans-splicing, Nat. Biotechnol., 20, 47, 10.1038/nbt0102-47 Llavona, 2017 Lorson, 2010, Mechanisms and therapeutic strategies, Hum. Mol. Genet., 19, R111, 10.1093/hmg/ddq147 Lukovic, 2015, Human iPSC derived disease model of MERTK-associated retinitis pigmentosa, Sci. Rep., 5, 12910, 10.1038/srep12910 Lukowski, 2019, A single-cell transcriptome atlas of the adult human retina, EMBO J., 38, 10.15252/embj.2018100811 Maeder, 2019, Development of a gene-editing approach to restore vision loss in Leber congenital amaurosis type 10, Nat. Med., 25, 229, 10.1038/s41591-018-0327-9 Magen, 2005, The importance of being divisible by three in alternative splicing, Nucleic Acids Res., 33, 5574, 10.1093/nar/gki858 Marco-Puche, 2019, RNA-seq perspectives to improve clinical diagnosis, Front. Genet., 10, 1152, 10.3389/fgene.2019.01152 Matera, 2014, A day in the life of the spliceosome, Nat. Rev. Mol. Cell Biol., 15, 108, 10.1038/nrm3742 Matlin, 2005, Understanding alternative splicing: towards a cellular code, Nat. Rev. Mol. Cell Biol., 6, 386, 10.1038/nrm1645 Matos, 2014, Therapeutic strategies based on modified U1 snRNAs and chaperones for Sanfilippo C splicing mutations, Orphanet J. Rare Dis., 9, 180, 10.1186/s13023-014-0180-y Maugeri, 1999, The 2588G-->C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease, Am. J. Hum. Genet., 64, 1024, 10.1086/302323 Mayer, 2016, Homozygosity mapping and whole-genome sequencing reveals a deep intronic PROM1 mutation causing cone-rod dystrophy by pseudoexon activation, Eur. J. Hum. Genet., 24, 459, 10.1038/ejhg.2015.144 McClements, 2013, Variations in opsin coding sequences cause X-linked cone dysfunction syndrome with myopia and dichromacy, Invest. Ophthalmol. Vis. Sci., 54, 1361, 10.1167/iovs.12-11156 McClorey, 2006, Antisense oligonucleotide-induced exon skipping restores dystrophin expression in vitro in a canine model of DMD, Gene Ther., 3, 1373, 10.1038/sj.gt.3302800 Mehmood, 2019, Systematic evaluation of differential splicing tools for RNA-seq studies, Brief Bioinform Mellough, 2019, An integrated transcriptional analysis of the developing human retina, Development, 146, dev169474, 10.1242/dev.169474 Mendell, 2016, Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy, Ann. Neurol., 79, 257, 10.1002/ana.24555 Mizrahi-Meissonnier, 2010, Variable retinal phenotypes caused by mutations in the X-linked photopigment gene array, Invest. Ophthalmol. Vis. Sci., 51, 3884, 10.1167/iovs.09-4592 Mukhopadhyay, 2006, Erosive vitreoretinopathy and wagner disease are caused by intronic mutations in CSPG2/Versican that result in an imbalance of splice variants, Invest. Ophthalmol. Vis. Sci., 47, 3565, 10.1167/iovs.06-0141 Murphy, 2016, The Musashi 1 controls the splicing of photoreceptor-specific exons in the vertebrate retina, PLoS Genet., 12, 10.1371/journal.pgen.1006256 Nakai, 1994, Construction of a novel database containing aberrant splicing mutations of mammalian genes, Gene, 141, 171, 10.1016/0378-1119(94)90567-3 Naryshkin, 2014, Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy, Science, 345, 688, 10.1126/science.1250127 Nathans, 1986, Molecular genetics of human color vision: the genes encoding blue, green, and red pigments, Science, 232, 193, 10.1126/science.2937147 Nellore, 2016, Human splicing diversity and the extent of unannotated splice junctions across human RNA-seq samples on the Sequence Read Archive, Genome Biol., 17, 266, 10.1186/s13059-016-1118-6 Orkin, 1981, Mutation in an intervening sequence splice junction in man, Proc. Natl. Acad. Sci. U. S. A., 78, 5041, 10.1073/pnas.78.8.5041 Pagani, 2003, New type of disease causing mutations: the example of the composite exonic regulatory elements of splicing in CFTR exon 12, Hum. Mol. Genet., 12, 1111, 10.1093/hmg/ddg131 Palacino, 2015, SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice, Nat. Chem. Biol., 11, 511, 10.1038/nchembio.1837 Parfitt, 2016, Using induced pluripotent stem cells to understand retinal ciliopathy disease mechanisms and develop therapies, Biochem. Soc. Trans., 44, 1245, 10.1042/BST20160156 Park, 2018, The expanding landscape of alternative splicing variation in human populations, Am. J. Hum. Genet., 102, 11, 10.1016/j.ajhg.2017.11.002 Peng, 2019, Molecular classification and comparative taxonomics of foveal and peripheral cells in primate retina, Cell, 176, 1222, 10.1016/j.cell.2019.01.004 Piovesan, 2016, 2016. GeneBase 1.1: a tool to summarize data from NCBI gene datasets and its application to an update of human gene statistics, Database, 2016, 10.1093/database/baw153 Piva, 2012, SpliceAid 2: a database of human splicing factors expression data and RNA target motifs, Hum. Mutat., 33, 81, 10.1002/humu.21609 Pulyakhina, 2015, SplicePie: a novel analytical approach for the detection of alternative, non-sequential and recursive splicing, Nucleic Acids Res., 43, 11068, 10.1093/nar/gkv1062 Raj, 2018, Integrative transcriptome analyses of the aging brain implicate altered splicing in Alzheimer's disease susceptibility, Nat. Genet., 50, 1584, 10.1038/s41588-018-0238-1 Ramsbottom, 2018, Targeted exon skipping of a CEP290 mutation rescues Joubert syndrome phenotypes in vitro and in a murine model, Proc. Natl. Acad. Sci. U. S. A., 115, 12489, 10.1073/pnas.1809432115 Ratnapriya, 2019, Retinal transcriptome and eQTL analyses identify genes associated with age-related macular degeneration, Nat. Genet., 51, 606, 10.1038/s41588-019-0351-9 Ratni, 2019, Rewriting the (tran)script: application to spinal muscular atrophy, Prog. Med. Chem., 58, 119, 10.1016/bs.pmch.2018.12.003 Rattner, 2001, A photoreceptor-specific cadherin is essential for the structural integrity of the outer segment and for photoreceptor survival, Neuron, 32, 775, 10.1016/S0896-6273(01)00531-1 Rattner, 2004, Proteolytic shedding of the extracellular domain of photoreceptor cadherin. Implications for outer segment assembly, J. Biol. Chem., 279, 42202, 10.1074/jbc.M407928200 Redmond, 1998, Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle, Nat. Genet., 20, 344, 10.1038/3813 Reed, 1985, Intron sequences involved in lariat formation during pre-mRNA splicing, Cell, 41, 95, 10.1016/0092-8674(85)90064-9 Reese, 1997, Improved splice site detection in Genie, J. Comput. Biol., 4, 311, 10.1089/cmb.1997.4.311 Rheaume, 2018, Single cell transcriptome profiling of retinal ganglion cells identifies cellular subtypes, Nat. Commun., 9, 2759, 10.1038/s41467-018-05134-3 Rimoldi, 2013, Dual role of G-runs and hnRNP F in the regulation of a mutation-activated pseudoexon in the fibrinogen Gamma-chain transcript, PloS One, 8, 10.1371/journal.pone.0059333 Rio Frio, 2009, A single-base substitution within an intronic repetitive element causes dominant retinitis pigmentosa with reduced penetrance, Hum. Mutat., 30, 1340, 10.1002/humu.21071 Rivera, 2000, A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration, Am. J. Hum. Genet., 67, 800, 10.1086/303090 Rogalska, 2016, Therapeutic activity of modified U1 core spliceosomal particles, Nat. Commun., 7, 11168, 10.1038/ncomms11168 Roosing, 2014, Causes and consequences of inherited cone disorders, Prog. Retin. Eye Res., 42, 1, 10.1016/j.preteyeres.2014.05.001 Rosenberg, 2015, Learning the sequence determinants of alternative splicing from millions of random sequences, Cell, 163, 698, 10.1016/j.cell.2015.09.054 Ruskin, 1984, Excision of an intact intron as a novel lariat structure during pre-mRNA splicing in vitro, Cell, 38, 317, 10.1016/0092-8674(84)90553-1 Růžičková, 2017, Mutations in spliceosomal proteins and retina degeneration, RNA Biol., 14, 544, 10.1080/15476286.2016.1191735 Sakabe, 2007, Sequence features responsible for intron retention in human, BMC Genom., 8, 59, 10.1186/1471-2164-8-59 Sakharkar, 2004, Distributions of exons and introns in the human genome, Silico Biol., 4, 387 Sangermano, 2016, Photoreceptor progenitor mRNA analysis reveals exon skipping resulting from the ABCA4 c.5461-10t→C mutation in Stargardt disease, Ophthalmology, 123, 1375, 10.1016/j.ophtha.2016.01.053 Sangermano, 2018, ABCA4 midigenes reveal the full splice spectrum of all reported noncanonical splice site variants in Stargardt disease, Genome Res., 28, 100, 10.1101/gr.226621.117 Sangermano, 2019, Deep-intronic ABCA4 variants explain missing heritability in Stargardt disease and allow correction of splice defects by antisense oligonucleotides, Genet Med, 10.1038/s41436-018-0414-9 Schmid, 2013, A gene therapeutic approach to correct splice defects with modified U1 and U6 snRNPs, Hum. Gene Ther., 24, 97, 10.1089/hum.2012.110 Schulz, 2017, Mutation spectrum of the ABCA4 gene in 335 Stargardt disease patients from a multicenter German Cohort-impact of selected deep intronic variants and common SNPs, Invest. Ophthalmol. Vis. Sci., 58, 394, 10.1167/iovs.16-19936 Schwartz, 2009, SROOGLE: webserver for integrative, user-friendly visualization of splicing signals, Nucleic Acids Res., 37, 189, 10.1093/nar/gkp320 Scotti, 2015, RNA mis-splicing in disease, Nat. Rev. Genet., 17, 19, 10.1038/nrg.2015.3 Shapiro, 1987, RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression, Nucleic Acids Res., 15, 7155, 10.1093/nar/15.17.7155 Shekhar, 2016, Comprehensive classification of retinal bipolar neurons by single-cell transcriptomics, Cell, 166, 1308, 10.1016/j.cell.2016.07.054 Slaugenhaupt, 2004, Rescue of a human mRNA splicing defect by the plant cytokinin kinetin, Hum. Mol. Genet., 13, 429, 10.1093/hmg/ddh046 Slijkerman, 2015, The pros and cons of vertebrate animal models for functional and therapeutic research on inherited retinal dystrophies, Prog. Retin. Eye Res., 48, 137, 10.1016/j.preteyeres.2015.04.004 Slijkerman, 2016, Antisense oligonucleotide-based splice correction for USH2A-associated retinal degeneration caused by a frequent deep-intronic mutation, Mol. Ther. Nucleic Acids, 5, e381, 10.1038/mtna.2016.89 Soemedi, 2017, Pathogenic variants that alter protein code often disrupt splicing, Nat Genet.49, 848, 10.1038/ng.3837 Soens, 2017, Leveraging splice-affecting variant predictors and a minigene validation system to identify Mendelian disease-causing variants among exon-captured variants of uncertain significance, Hum. Mutat., 38, 1521, 10.1002/humu.23294 Sothilingam, 2015, Retinitis pigmentosa: impact of different Pde6a point mutations on the disease phenotype, Hum. Mol. Genet., 24, 5486, 10.1093/hmg/ddv275 Stingl, 2017, CDHR1 mutations in retinal dystrophies, Sci. Rep., 7, 6992, 10.1038/s41598-017-07117-8 Sullivan, 2006, Prevalence of disease-causing mutations in families with autosomal dominant retinitis pigmentosa: a screen of known genes in 200 families, Invest. Ophthalmol. Vis. Sci., 47, 3052, 10.1167/iovs.05-1443 Takahara, 2002, Order of intron removal influences multiple splice outcomes, including a two-exon skip, in a COL5A1 acceptorsite mutation that results in abnormal pro-alpha1(V) N-propeptides and Ehlers-Danlos syndrome type I, Am. J. Hum. Genet., 71, 451, 10.1086/342099 Tammaro, 2014, BRCA1 EXON 11, a CERES (composite regulatory element of splicing) element involved in splice regulation, Int. J. Mol. Sci., 15, 13045, 10.3390/ijms150713045 Tan, 2004, Expression of cone-photoreceptor-specific antigens in a cell line derived from retinal tumors in transgenic mice, Invest. Ophthalmol. Vis. Sci., 45, 764, 10.1167/iovs.03-1114 Tanackovic, 2011, PRPF mutations are associated with generalized defects in spliceosome formation and pre-mRNA splicing in patients with retinitis pigmentosa, Hum. Mol. Genet., 20, 2116, 10.1093/hmg/ddr094 Tanner, 2009, Therapeutic strategy to rescue mutation-induced exon skipping in rhodopsin by adaptation of U1 snRNA, Hum. Mutat., 30, 255, 10.1002/humu.20861 Thorvaldsdóttir, 2013, Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration, Briefings Bioinf., 14, 178, 10.1093/bib/bbs017 Tucker, 2015, Using patient-specific induced pluripotent stem cells to interrogate the pathogenicity of a novel retinal pigment epithelium-specific 65 kDa cryptic splice site mutation and confirm eligibility for enrollment into a clinical gene augmentation trial, Transl. Res., 166, 740, 10.1016/j.trsl.2015.08.007 Turunen, 2013, The significant other: splicing by the minor spliceosome, Wiley. Interdis. Rev. RNA, 4, 61, 10.1002/wrna.1141 Ueyama, 2012, Unique haplotype in exon 3 of cone opsin mRNA affects splicing of its precursor, leading to congenital color vision defect, Biochem. Biophys. Res. Commun., 424, 152, 10.1016/j.bbrc.2012.06.094 Vaché, 2012, Usher syndrome type 2 caused by activation of an USH2A pseudoexon: implications for diagnosis and therapy, Hum. Mutat., 33, 104, 10.1002/humu.21634 van den Hurk, 2003, Novel types of mutation in the choroideremia (CHM) gene: a full-length L1 insertion and an intronic mutation activating a cryptic exon, Hum. Genet., 113, 268, 10.1007/s00439-003-0970-0 Vervoort, 2000, Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa, Nat. Genet., 25, 462, 10.1038/78182 Voigt, 2019, Molecular characterization of foveal versus peripheral human retina by single-cell RNA sequencing, Exp. Eye Res., 184, 234, 10.1016/j.exer.2019.05.001 Wan, 2011, Dynamic usage of alternative splicing exons during mouse retina development, Nucleic Acids Res., 39, 7920, 10.1093/nar/gkr545 Wang, 2007, Splicing in disease: disruption of the splicing code and the decoding machinery, Nat. Rev. Genet., 8, 749, 10.1038/nrg2164 Wang, 2004, Systematic identification and analysis of exonic splicing silencers, Cell, 119, 831, 10.1016/j.cell.2004.11.010 Wang, 2006, General and specific functions of exonic splicing silencers in splicing control, Mol. Cell., 23, 61, 10.1016/j.molcel.2006.05.018 Webb, 2012, Deep intronic mutation in OFD1, identified by targeted genomic next-generation sequencing, causes a severe form of X-linked retinitis pigmentosa (RP23), Hum. Mol. Genet., 21, 3647, 10.1093/hmg/dds194 Weisschuh, 2020, Deep-intronic variants in CNGB3 cause achromatopsia by pseudoexon activation, Hum. Mutat., 41, 255, 10.1002/humu.23920 Weng, 1999, Insights into the function of Rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in abcr knockout mice, Cell, 98, 13, 10.1016/S0092-8674(00)80602-9 Wong, 2016, Intron retention in mRNA: No longer nonsense: known and putative roles of intron retention in normal and disease biology, Bioessays, 38, 41, 10.1002/bies.201500117 Xiong, 2015, RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease, Science, 347, 1254806, 10.1126/science.1254806 Yang, 2008, Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice, J. Clin. Invest., 118, 2908 Yardley, 2004, Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC), Invest. Ophthalmol. Vis. Sci., 45, 3683, 10.1167/iovs.04-0550 Yeo, 2004, Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals, J. Comput. Biol., 11, 377, 10.1089/1066527041410418 Yoshida, 2014, The use of induced pluripotent stem cells to reveal pathogenic gene mutations and explore treatments for retinitis pigmentosa, Mol. Brain, 7, 45, 10.1186/1756-6606-7-45 Yoshida, 2015, Rectifier of aberrant mRNA splicing recovers tRNA modification in familial dysautonomia, Proc. Natl. Acad. Sci. U. S. A., 112, 2764, 10.1073/pnas.1415525112 Zaneveld, 2015, Comprehensive analysis of patients with Stargardt macular dystrophy reveals new genotype-phenotype correlations and unexpected diagnostic revisions, Genet. Med., 17, 262, 10.1038/gim.2014.174 Zelinger, 2018, RNA biology in retinal development and disease, Trends Genet., 34, 341, 10.1016/j.tig.2018.01.002 Zernant, 2014, Analysis of the ABCA4 genomic locus in Stargardt disease, Hum. Mol. Genet., 23, 6797, 10.1093/hmg/ddu396 Zernant, 2017, Frequent hypomorphic alleles account for a significant fraction of ABCA4 disease and distinguish it from age-related macular degeneration, J. Med. Genet., 54, 404, 10.1136/jmedgenet-2017-104540 Zhang, 2015, Identification of common genetic variants controlling transcript isoform variation in human whole blood, Nat. Genet., 47, 345, 10.1038/ng.3220 Zhang, 2018, Gene therapy using a miniCEP290 fragment delays photoreceptor degeneration in a mouse model of leber congenital amaurosis, Hum. Gene Ther., 29, 42, 10.1089/hum.2017.049 Zhao, 2009, Autosomal-dominant retinitis pigmentosa caused by a mutation in SNRNP200, a gene required for unwinding of U4/U6 snRNAs, Am. J. Hum. Genet., 85, 617, 10.1016/j.ajhg.2009.09.020 Zhou, 2014, Transcriptome analysis of alternative splicing events regulated by SRSF10 reveals position-dependent splicing modulation, Nucleic Acids Res., 42, 4019, 10.1093/nar/gkt1387 Zhuang, 1986, A compensatory base change in U1 snRNA suppresses a 5' splice site mutation, Cell, 46, 827, 10.1016/0092-8674(86)90064-4