{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRPE65 is a critical retinoid isomerase expressed predominantly in the retinal pigment epithelium that catalyzes the conversion of all‐trans‐retinyl esters into 11‑cis‑retinol—a reaction essential for regenerating the chromophore 11‑cis‑retinal required by both rod and cone photoreceptors. This enzyme’s activity underpins the visual (retinoid) cycle and is dependent on its precise membrane association and structural integrity, which are maintained by several conserved amino acid residues and post‐translational modifications (e.g., palmitoylation of key cysteines). Its highly conserved function has been elucidated through biochemical assays, mutagenesis studies, and structural modeling, thereby establishing RPE65’s central role in phototransduction and visual pigment regeneration."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDeficiencies in RPE65 function—often resulting from missense, nonsense, or splicing mutations—lead to a spectrum of inherited retinal dystrophies such as Leber congenital amaurosis (LCA) and retinitis pigmentosa. The loss of isomerohydrolase activity disrupts the regeneration of the 11‑cis‑chromophore, which ultimately impairs visual function and can result in photoreceptor degeneration. These insights have fueled the development of gene augmentation therapies using adeno‐associated viral vectors and alternative non‐viral delivery systems that restore RPE65 expression, thereby improving retinal sensitivity and visual outcomes in both animal models and human clinical trials."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its established role in the visual cycle, ongoing research continues to refine our understanding of RPE65 through advanced diagnostic sequencing, genotype–phenotype correlation studies, and exploration of alternative delivery strategies—including compacted DNA nanoparticles and microRNA‐based differentiation—for both ocular and potential extra‐ocular functions. In some studies, RPE65 expression has been detected in non‐retinal tissues such as epidermal keratinocytes, suggesting an expanded role in retinoid metabolism. Moreover, comparative analyses across species have revealed that variations in RPE65’s specific activity may relate to the differing visual requirements of rod‐ versus cone‐dominant retinas. Collectively, these developments underscore the importance of RPE65 not only as a vital enzyme for photopigment regeneration but also as a promising target for therapeutic intervention in retinal degenerative diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "32", "end_ref": "45"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "M J Simovich, B Miller, H Ezzeldin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Four novel mutations in the RPE65 gene in patients with Leber congenital amaurosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.1168"}], "href": "https://doi.org/10.1002/humu.1168"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11462243"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11462243"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Debra A Thompson, Christina L McHenry, Yun Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Retinal dystrophy due to paternal isodisomy for chromosome 1 or chromosome 2, with homoallelism for mutations in RPE65 or MERTK, respectively."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/338455"}], "href": "https://doi.org/10.1086/338455"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11727200"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11727200"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Joost Felius, Debra A Thompson, Naheed W Khan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical course and visual function in a family with mutations in the RPE65 gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arch Ophthalmol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1001/archopht.120.1.55"}], "href": "https://doi.org/10.1001/archopht.120.1.55"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11786058"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11786058"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Kholoud Al-Khayer, Stephanie Hagstrom, Gayle Pauer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thirty-year follow-up of a patient with leber congenital amaurosis and novel RPE65 mutations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Ophthalmol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/S0002-9394(03)00913-9"}], "href": "https://doi.org/10.1016/S0002-9394(03"}, {"type": "t", "text": "00913-9) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14962443"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14962443"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Gabriele Hinterhuber, Karla Cauza, Karin Brugger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RPE65 of retinal pigment epithelium, a putative receptor molecule for plasma retinol-binding protein, is expressed in human keratinocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Invest Dermatol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1046/j.0022-202X.2004.22216.x"}], "href": "https://doi.org/10.1046/j.0022-202X.2004.22216.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15009723"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15009723"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Samuel G Jacobson, Tomas S Aleman, Artur V Cideciyan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0500646102"}], "href": "https://doi.org/10.1073/pnas.0500646102"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15837919"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15837919"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yusuke Takahashi, Gennadiy Moiseyev, Ying Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of conserved histidines and glutamic acid as key residues for isomerohydrolase activity of RPE65, an enzyme of the visual cycle in the retinal pigment epithelium."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2005.09.002"}], "href": "https://doi.org/10.1016/j.febslet.2005.09.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16198348"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16198348"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "J C Booij, R J Florijn, J B ten Brink, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of mutations in the AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 genes in patients with juvenile retinitis pigmentosa."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Genet (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jmg.2005.035121"}], "href": "https://doi.org/10.1136/jmg.2005.035121"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16272259"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16272259"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Leila El Matri, Aude Ambresin, Daniel F Schorderet, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phenotype of three consanguineous Tunisian families with early-onset retinal degeneration caused by an R91W homozygous mutation in the RPE65 gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Graefes Arch Clin Exp Ophthalmol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00417-005-0096-2"}], "href": "https://doi.org/10.1007/s00417-005-0096-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16518657"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16518657"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Yusuke Takahashi, Ying Chen, Gennadiy Moiseyev, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Two point mutations of RPE65 from patients with retinal dystrophies decrease the stability of RPE65 protein and abolish its isomerohydrolase activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M603725200"}], "href": "https://doi.org/10.1074/jbc.M603725200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16754667"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16754667"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Samuel G Jacobson, Artur V Cideciyan, Tomas S Aleman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RDH12 and RPE65, visual cycle genes causing leber congenital amaurosis, differ in disease expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Invest Ophthalmol Vis Sci (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1167/iovs.06-0599"}], "href": "https://doi.org/10.1167/iovs.06-0599"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17197551"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17197551"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Robert K Koenekoop, Irma Lopez, Anneke I den Hollander, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic testing for retinal dystrophies and dysfunctions: benefits, dilemmas and solutions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Exp Ophthalmol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1442-9071.2007.01534.x"}], "href": "https://doi.org/10.1111/j.1442-9071.2007.01534.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17651254"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17651254"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Francesca Simonelli, Carmela Ziviello, Francesco Testa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical and molecular genetics of Leber's congenital amaurosis: a multicenter study of Italian patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Invest Ophthalmol Vis Sci (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1167/iovs.07-0068"}], "href": "https://doi.org/10.1167/iovs.07-0068"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17724218"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17724218"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Samuel G Jacobson, Tomas S Aleman, Artur V Cideciyan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human cone photoreceptor dependence on RPE65 isomerase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0706367104"}], "href": "https://doi.org/10.1073/pnas.0706367104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17848510"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17848510"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Gennadiy Moiseyev, Yusuke Takahashi, Ying Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RPE65 from cone-dominant chicken is a more efficient isomerohydrolase compared with that from rod-dominant species."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M703654200"}], "href": "https://doi.org/10.1074/jbc.M703654200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18216020"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18216020"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Samuel G Jacobson, Artur V Cideciyan, Tomas S Aleman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Photoreceptor layer topography in children with leber congenital amaurosis caused by RPE65 mutations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Invest Ophthalmol Vis Sci (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1167/iovs.08-2121"}], "href": "https://doi.org/10.1167/iovs.08-2121"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18539930"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18539930"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Birgit Lorenz, Eugenia Poliakov, Maria Schambeck, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A comprehensive clinical and biochemical functional study of a novel RPE65 hypomorphic mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Invest Ophthalmol Vis Sci (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1167/iovs.07-1671"}], "href": "https://doi.org/10.1167/iovs.07-1671"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18599565"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18599565"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Grzegorz Bereta, Philip D Kiser, Marcin Golczak, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Impact of retinal disease-associated RPE65 mutations on retinoid isomerization."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi800905v"}], "href": "https://doi.org/10.1021/bi800905v"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18722466"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18722466"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "William W Hauswirth, Tomas S Aleman, Shalesh Kaushal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Gene Ther (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1089/hum.2008.107"}], "href": "https://doi.org/10.1089/hum.2008.107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18774912"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18774912"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Yusuke Takahashi, Gennadiy Moiseyev, Zsolt Ablonczy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of a novel palmitylation site essential for membrane association and isomerohydrolase activity of RPE65."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M807248200"}], "href": "https://doi.org/10.1074/jbc.M807248200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19049981"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19049981"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Samuel G Jacobson, Tomas S Aleman, Artur V Cideciyan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Defining the residual vision in leber congenital amaurosis caused by RPE65 mutations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Invest Ophthalmol Vis Sci (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1167/iovs.08-2696"}], "href": "https://doi.org/10.1167/iovs.08-2696"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19117922"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19117922"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Periasamy Sundaresan, P Vijayalakshmi, Stewart Thompson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations that are a common cause of Leber congenital amaurosis in northern America are rare in southern India."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Vis (2009)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19753312"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19753312"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "T Michael Redmond, Eugenia Poliakov, Stephanie Kuo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RPE65, visual cycle retinol isomerase, is not inherently 11-cis-specific: support for a carbocation mechanism of retinol isomerization."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.027458"}], "href": "https://doi.org/10.1074/jbc.M109.027458"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19920137"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19920137"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Sirichai Pasadhika, Gerald A Fishman, Edwin M Stone, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differential macular morphology in patients with RPE65-, CEP290-, GUCY2D-, and AIPL1-related Leber congenital amaurosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Invest Ophthalmol Vis Sci (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1167/iovs.09-3734"}], "href": "https://doi.org/10.1167/iovs.09-3734"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19959640"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19959640"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Artur V Cideciyan "}, {"type": "b", "children": [{"type": "t", "text": "Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Prog Retin Eye Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.preteyeres.2010.04.002"}], "href": "https://doi.org/10.1016/j.preteyeres.2010.04.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20399883"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20399883"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Graeme Richard Clark, Paul Crowe, Dorota Muszynska, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Development of a diagnostic genetic test for simplex and autosomal recessive retinitis pigmentosa."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ophthalmology (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ophtha.2010.02.029"}], "href": "https://doi.org/10.1016/j.ophtha.2010.02.029"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20591486"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20591486"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Richard G Weleber, Michel Michaelides, Karmen M Trzupek, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The phenotype of Severe Early Childhood Onset Retinal Dystrophy (SECORD) from mutation of RPE65 and differentiation from Leber congenital amaurosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Invest Ophthalmol Vis Sci (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1167/iovs.10-6106"}], "href": "https://doi.org/10.1167/iovs.10-6106"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20811047"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20811047"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Patrik Schatz, Markus Preising, Birgit Lorenz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Fundus albipunctatus associated with compound heterozygous mutations in RPE65."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ophthalmology (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ophtha.2010.09.005"}], "href": "https://doi.org/10.1016/j.ophtha.2010.09.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21211845"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21211845"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Sara J Bowne, Marian M Humphries, Lori S Sullivan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A dominant mutation in RPE65 identified by whole-exome sequencing causes retinitis pigmentosa with choroidal involvement."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ejhg.2011.86"}], "href": "https://doi.org/10.1038/ejhg.2011.86"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21654732"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21654732"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Samuel G Jacobson, Artur V Cideciyan, Ramakrishna Ratnakaram, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arch Ophthalmol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1001/archophthalmol.2011.298"}], "href": "https://doi.org/10.1001/archophthalmol.2011.298"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21911650"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21911650"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Fei Xu, Qiang Dong, Liang Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel RPE65 mutations associated with Leber congenital amaurosis in Chinese patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Vis (2012)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22509104"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22509104"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Adarsha Koirala, Rasha S Makkia, Shannon M Conley, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S/MAR-containing DNA nanoparticles promote persistent RPE gene expression and improvement in RPE65-associated LCA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddt013"}], "href": "https://doi.org/10.1093/hmg/ddt013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23335596"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23335596"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Soon Won Choi, Jae-Jun Kim, Min-Soo Seo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-410 Inhibition Induces RPE Differentiation of Amniotic Epithelial Stem Cells via Overexpression of OTX2 and RPE65."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cell Rev Rep (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12015-014-9568-2"}], "href": "https://doi.org/10.1007/s12015-014-9568-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25351180"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25351180"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Satoshi Katagiri, Takaaki Hayashi, Mineo Kondo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RPE65 Mutations in Two Japanese Families with Leber Congenital Amaurosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ophthalmic Genet (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3109/13816810.2014.991931"}], "href": "https://doi.org/10.3109/13816810.2014.991931"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25495949"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25495949"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Budd A Tucker, Cathryn M Cranston, Kristin A Anfinson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "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."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Transl Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.trsl.2015.08.007"}], "href": "https://doi.org/10.1016/j.trsl.2015.08.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26364624"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26364624"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Galuh D N Astuti, Mette Bertelsen, Markus N Preising, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ejhg.2015.241"}], "href": "https://doi.org/10.1038/ejhg.2015.241"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26626312"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26626312"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Satoshi Katagiri, Katsuhiro Hosono, Takaaki Hayashi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Early onset flecked retinal dystrophy associated with new compound heterozygous "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "RPE65"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " variants."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Vis (2018)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29681726"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29681726"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "Mark E Pennesi, Richard G Weleber, Paul Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Results at 5 Years After Gene Therapy for RPE65-Deficient Retinal Dystrophy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Gene Ther (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1089/hum.2018.014"}], "href": "https://doi.org/10.1089/hum.2018.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29869534"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29869534"}]}, {"type": "r", "ref": 39, "children": [{"type": "t", "text": "Ruben Jauregui, Karen Sophia Park, Stephen H Tsang "}, {"type": "b", "children": [{"type": "t", "text": "Two-year progression analysis of RPE65 autosomal dominant retinitis pigmentosa."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ophthalmic Genet (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/13816810.2018.1484929"}], "href": "https://doi.org/10.1080/13816810.2018.1484929"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29947567"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29947567"}]}, {"type": "r", "ref": 40, "children": [{"type": "t", "text": "Neruban Kumaran, Gary S Rubin, Angelos Kalitzeos, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A Cross-Sectional and Longitudinal Study of Retinal Sensitivity in RPE65-Associated Leber Congenital Amaurosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Invest Ophthalmol Vis Sci (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1167/iovs.18-23873"}], "href": "https://doi.org/10.1167/iovs.18-23873"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30025081"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30025081"}]}, {"type": "r", "ref": 41, "children": [{"type": "t", "text": "Daniel C Chung, Mette Bertelsen, Birgit Lorenz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Natural History of Inherited Retinal Dystrophy Due to Biallelic Mutations in the RPE65 Gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Ophthalmol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajo.2018.09.024"}], "href": "https://doi.org/10.1016/j.ajo.2018.09.024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30268864"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30268864"}]}, {"type": "r", "ref": 42, "children": [{"type": "t", "text": "Shiqiang Li, Xueshan Xiao, Zhen Yi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RPE65 mutation frequency and phenotypic variation according to exome sequencing in a tertiary centre for genetic eye diseases in China."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Ophthalmol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/aos.14181"}], "href": "https://doi.org/10.1111/aos.14181"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31273949"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31273949"}]}, {"type": "r", "ref": 43, "children": [{"type": "t", "text": "Eugenia Poliakov, Sheetal Uppal, Igor B Rogozin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Evolutionary aspects and enzymology of metazoan carotenoid cleavage oxygenases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta Mol Cell Biol Lipids (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbalip.2020.158665"}], "href": "https://doi.org/10.1016/j.bbalip.2020.158665"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32061750"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32061750"}]}, {"type": "r", "ref": 44, "children": [{"type": "t", "text": "William S Gange, Robert A Sisk, Cagri G Besirli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Perifoveal Chorioretinal Atrophy after Subretinal Voretigene Neparvovec-rzyl for RPE65-Mediated Leber Congenital Amaurosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ophthalmol Retina (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.oret.2021.03.016"}], "href": "https://doi.org/10.1016/j.oret.2021.03.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33838313"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33838313"}]}, {"type": "r", "ref": 45, "children": [{"type": "t", "text": "Manar Aoun, Ilaria Passerini, Pietro Chiurazzi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inherited Retinal Diseases Due to "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "RPE65"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " Variants: From Genetic Diagnostic Management to Therapy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms22137207"}], "href": "https://doi.org/10.3390/ijms22137207"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34281261"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34281261"}]}]}]}