Nationwide genetic analysis of more than 600 families with inherited eye diseases in Argentina

Schlottmann, Patricio G.; Luna, Catalina; Labat, Natalia; Yadarola, María Belén; Bainttein, Silvina; Espósito, Evangelina; Ibáñez, Agustina; Barbaro, Evangelina; Mendiara, Alejandro Álvarez; Picotti, Carolina; Misisian, Andrea Chirino; Andreussi, Luciana; Gras, Julieta; Capalbo, Luciana; Visotto, Mauro; Dipierri, José Edgardo; Alcoba, Emilio; Gabrielli, Laura Fernández; Ávila, Sílvia; Aucar, María Emilia; Martin, Daniel M.; Ormaechea, Gerardo Juan; Inga, M. Eugenia; Francone, A; Charles, Martin; Zompa, Tamara; Pérez, P. Rodríguez; Lotersztein, Vanesa; Nuova, Pedro; Canonero, Ivana; Mahroo, Omar A.; Michaelides, Michel; Arno, Gavin; Varela, Malena Daich

doi:10.1038/s41525-023-00352-1

Cited by 3 publications

(1 citation statement)

References 74 publications

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“…Triple knockout mice abca4(-/-)rdh8(-/-)rdh12(-/-) raised under cyclic light develop retinal degeneration at the age of 6 weeks, whereas at least 3 months are needed to demonstrate a similar level of retinal degeneration for double knockout mice abca4(-/-)rdh8(-/-) [ 113 ]. Mutations of RDH12 can cause early onset severe cone-rod dystrophy, Leber congenital amaurosis, retinitis pigmentosa, and pseudocoloboma-like maculopathy [ 114 , 115 , 116 , 117 , 118 ].…”

Section: Discussionmentioning

confidence: 99%

Scavenging of Cation Radicals of the Visual Cycle Retinoids by Lutein, Zeaxanthin, Taurine, and Melanin

Rozanowska,

Edge,

Land

et al. 2023

IJMS

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In the retina, retinoids involved in vision are under constant threat of oxidation, and their oxidation products exhibit deleterious properties. Using pulse radiolysis, this study determined that the bimolecular rate constants of scavenging cation radicals of retinoids by taurine are smaller than 2 × 107 M−1s−1 whereas lutein scavenges cation radicals of all three retinoids with the bimolecular rate constants approach the diffusion-controlled limits, while zeaxanthin is only 1.4–1.6-fold less effective. Despite that lutein exhibits greater scavenging rate constants of retinoid cation radicals than other antioxidants, the greater concentrations of ascorbate in the retina suggest that ascorbate may be the main protectant of all visual cycle retinoids from oxidative degradation, while α-tocopherol may play a substantial role in the protection of retinaldehyde but is relatively inefficient in the protection of retinol or retinyl palmitate. While the protection of retinoids by lutein and zeaxanthin appears inefficient in the retinal periphery, it can be quite substantial in the macula. Although the determined rate constants of scavenging the cation radicals of retinol and retinaldehyde by dopa-melanin are relatively small, the high concentration of melanin in the RPE melanosomes suggests they can be scavenged if they are in proximity to melanin-containing pigment granules.

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Section: Discussionmentioning

confidence: 99%

Scavenging of Cation Radicals of the Visual Cycle Retinoids by Lutein, Zeaxanthin, Taurine, and Melanin

Rozanowska,

Edge,

Land

et al. 2023

IJMS

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PHYH c.678+5G>T Leads to In-Frame Exon Skipping and Is Associated With Attenuated Refsum Disease

Daich Varela,

Schiff,

Malka

et al. 2024

Invest. Ophthalmol. Vis. Sci.

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Purpose To investigate the molecular effect of the variant PHYH :c.678+5G>T. This variant has conflicting interpretations in the ClinVar database and a maximum allele frequency of 0.0045 in the South Asian population in gnomAD. Methods We recruited patients from Moorfields Eye Hospital (London, UK) and Buenos Aires, Argentina, who were diagnosed with retinitis pigmentosa and found to have biallelic variants in PHYH , with at least one being c.678+5G>T. Total RNA was purified from PaxGene RNA-stabilized whole-blood samples, followed by reverse transcription to cDNA, PCR amplification of the canonical PHYH transcript, Oxford Nanopore Technologies library preparation, and single-molecule amplicon sequencing. Results Four patients provided a blood sample. One patient had isolated retinitis pigmentosa and three had mild extraocular findings. Blood phytanic acid levels were normal in two patients, mildly elevated in one, and markedly high in the fourth. Retinal evaluation showed an intact ellipsoid zone as well as preserved autofluorescence in the macular region in three of the four patients. In all patients, we observed in-frame skipping of exons 5 and 6 in 31.1% to 88.4% of the amplicons and a smaller proportion (0% to 11.3% of amplicons) skipping exon 6 only. Conclusions We demonstrate a significant effect of PHYH :c.678+5G>T on splicing of the canonical transcript. The in-frame nature of this may be in keeping with a mild presentation and higher prevalence in the general population. These data support the classification of the variant as pathogenic, and patients harboring a biallelic genotype should undergo phytanic acid testing.

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Optogenetics and Targeted Gene Therapy for Retinal Diseases: Unravelling the Fundamentals, Applications, and Future Perspectives

Kulbay,

Tuli,

Akdag

et al. 2024

JCM

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With a common aim of restoring physiological function of defective cells, optogenetics and targeted gene therapies have shown great clinical potential and novelty in the branch of personalized medicine and inherited retinal diseases (IRDs). The basis of optogenetics aims to bypass defective photoreceptors by introducing opsins with light-sensing capabilities. In contrast, targeted gene therapies, such as methods based on CRISPR-Cas9 and RNA interference with noncoding RNAs (i.e., microRNA, small interfering RNA, short hairpin RNA), consists of inducing normal gene or protein expression into affected cells. Having partially leveraged the challenges limiting their prompt introduction into the clinical practice (i.e., engineering, cell or tissue delivery capabilities), it is crucial to deepen the fields of knowledge applied to optogenetics and targeted gene therapy. The aim of this in-depth and novel literature review is to explain the fundamentals and applications of optogenetics and targeted gene therapies, while providing decision-making arguments for ophthalmologists. First, we review the biomolecular principles and engineering steps involved in optogenetics and the targeted gene therapies mentioned above by bringing a focus on the specific vectors and molecules for cell signalization. The importance of vector choice and engineering methods are discussed. Second, we summarize the ongoing clinical trials and most recent discoveries for optogenetics and targeted gene therapies for IRDs. Finally, we then discuss the limits and current challenges of each novel therapy. We aim to provide for the first time scientific-based explanations for clinicians to justify the specificity of each therapy for one disease, which can help improve clinical decision-making tasks.

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Nationwide genetic analysis of more than 600 families with inherited eye diseases in Argentina

Cited by 3 publications

References 74 publications

Scavenging of Cation Radicals of the Visual Cycle Retinoids by Lutein, Zeaxanthin, Taurine, and Melanin

Scavenging of Cation Radicals of the Visual Cycle Retinoids by Lutein, Zeaxanthin, Taurine, and Melanin

PHYH c.678+5G>T Leads to In-Frame Exon Skipping and Is Associated With Attenuated Refsum Disease

Optogenetics and Targeted Gene Therapy for Retinal Diseases: Unravelling the Fundamentals, Applications, and Future Perspectives

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Nationwide genetic analysis of more than 600 families with inherited eye diseases in Argentina

Cited by 3 publications

References 74 publications

Scavenging of Cation Radicals of the Visual Cycle Retinoids by Lutein, Zeaxanthin, Taurine, and Melanin

Scavenging of Cation Radicals of the Visual Cycle Retinoids by Lutein, Zeaxanthin, Taurine, and Melanin

PHYH c.678+5G&gt;T Leads to In-Frame Exon Skipping and Is Associated With Attenuated Refsum Disease

Optogenetics and Targeted Gene Therapy for Retinal Diseases: Unravelling the Fundamentals, Applications, and Future Perspectives

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Product

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PHYH c.678+5G>T Leads to In-Frame Exon Skipping and Is Associated With Attenuated Refsum Disease