GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies

Bouzia, Zaina; Georgiou, Michalis; Hull, Sarah; Robson, Anthony G.; Fujinami, Kaoru; Rotsos, Tryfon; Pontikos, Nikolas; Arno, Gavin; Webster, Andrew R.; Hardcastle, Alison J.; Fiorentino, Alessia; Michaelides, Michel

doi:10.1016/j.ajo.2019.10.019

Cited by 47 publications

(48 citation statements)

References 37 publications

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“…In the homozygous Gucy2e tm1Gar model, D 50 was >12 months (Figure 6), indicating very slow rod PR cell loss, while cone cell numbers decreased rapidly to 33% of controls in 5 weeks [191]. Cone loss with rod preservation has been observed in Leber congenital amaurosis cases linked to variants of the human Gucy2e ortholog, GUCY2D [192]. However, Gucy2e tm1Gar mice are not considered to model this disease because rod ERG function, though diminished, is still detectable [191].…”

Section: Category 02: Visual Transductionmentioning

confidence: 91%

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Collin

Gogna

Chang

et al. 2020

Cells

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Inherited retinal degeneration (RD) leads to the impairment or loss of vision in millions of individuals worldwide, most frequently due to the loss of photoreceptor (PR) cells. Animal models, particularly the laboratory mouse, have been used to understand the pathogenic mechanisms that underlie PR cell loss and to explore therapies that may prevent, delay, or reverse RD. Here, we reviewed entries in the Mouse Genome Informatics and PubMed databases to compile a comprehensive list of monogenic mouse models in which PR cell loss is demonstrated. The progression of PR cell loss with postnatal age was documented in mutant alleles of genes grouped by biological function. As anticipated, a wide range in the onset and rate of cell loss was observed among the reported models. The analysis underscored relationships between RD genes and ciliary function, transcription-coupled DNA damage repair, and cellular chloride homeostasis. Comparing the mouse gene list to human RD genes identified in the RetNet database revealed that mouse models are available for 40% of the known human diseases, suggesting opportunities for future research. This work may provide insight into the molecular players and pathways through which PR degenerative disease occurs and may be useful for planning translational studies.

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Section: Category 02: Visual Transductionmentioning

confidence: 91%

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Collin

Gogna

Chang

et al. 2020

Cells

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“…Clinical presentation includes severe congenital/early infancy visual loss, nystagmus, amaurotic pupils and a markedly abnormal or undetectable full-field electroretinogram (ERG) [ 1 ]. The most common causative genes are CEP290 [ 2 ], GUCY2D [ 3 ], CRB1 [ 4 ], and RPE65 [ 5 – 8 ] . In total, the reported LCA/EOSRD-associated genes (n = 25) account for approximately 70–80% of cases [ 6 , 7 ], with more genes yet to be identified.…”

Section: Introductionmentioning

confidence: 99%

Extending the phenotypic spectrum of PRPF8, PRPH2, RP1 and RPGR, and the genotypic spectrum of early-onset severe retinal dystrophy

Georgiou

Ali

Yang

et al. 2021

Orphanet J Rare Dis

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Purpose To present the detailed retinal phenotype of patients with Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy (LCA/EOSRD) caused by sequence variants in four genes, either not (n = 1) or very rarely (n = 3) previously associated with the disease. Methods Retrospective case series of LCA/EOSRD from four pedigrees. Chart review of clinical notes, multimodal retinal imaging, electrophysiology, and molecular genetic testing at a single tertiary referral center (Moorfields Eye Hospital, London, UK). Results The mean age of presentation was 3 months of age, with disease onset in the first year of life in all cases. Molecular genetic testing revealed the following disease-causing variants: PRPF8 (heterozygous c.5804G > A), PRPH2 (homozygous c.620_627delinsTA, novel variant), RP1 (homozygous c.4147_4151delGGATT, novel variant) and RPGR (heterozygous c.1894_1897delGACA). PRPF8, PRPH2, and RP1 variants have very rarely been reported, either as unique cases or case reports, with limited clinical data presented. RPGR variants have not previously been associated with LCA/EOSRD. Clinical history and detailed retinal imaging are presented. Conclusions The reported cases extend the phenotypic spectrum of PRPF8-, PRPH2-, RP1-, and RPGR-associated disease, and the genotypic spectrum of LCA/EOSRD. The study highlights the importance of retinal and functional phenotyping, and the importance of specific genetic diagnosis to potential future therapy.

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“…It is difficult to compare the phenotypes of these patients as they are of different ages (7-year-old boy and 42-year-old woman, respectively), and we did not have full data about the course of the disease in the infancy in the female patient. Studies on a group of 21 patients with molecularly confirmed LCA1 revealed the relatively preserved photoreceptor structure over a broad age range indicating a wide therapeutic window for gene therapy trials [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Novel gene variants in Polish patients with Leber congenital amaurosis (LCA)

Skorczyk-Werner

Niedziela

Stopa

et al. 2020

Orphanet J Rare Dis

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Background Leber congenital amaurosis (LCA) is a rare retinal disease that is the most frequent cause of congenital blindness in children and the most severe form of inherited retinal dystrophies. To date, 25 genes have been implicated in the pathogenesis of LCA. As gene therapy is becoming available, the identification of potential treatment candidates is crucial. The aim of the study was to report the molecular basis of Leber congenital amaurosis in 22 Polish families. Methods Single Nucleotide Polymorphism-microarray for LCA genes or Next Generation Sequencing diagnostic panel for LCA genes (or both tests) were performed to identify potentially pathogenic variants. Bidirectional Sanger sequencing was carried out for validation and segregation analysis of the variants identified within the families. Results The molecular background was established in 22 families. From a total of 24 identified variants, 23 were predicted to affect protein-coding or splicing, including 10 novel variants. The variants were identified in 7 genes: CEP290, GUCY2D, RPE65, NMNAT1, CRB1, RPGRIP1, and CRX. More than one-third of the patients, with clinical LCA diagnosis confirmed by the results of molecular analysis, appeared to be affected with a severe form of the disease: LCA10 caused by the CEP290 gene variants. Intronic mutation c.2991+1655A>G in the CEP290 gene was the most frequent variant identified in the studied group. Conclusions This study provides the first molecular genetic characteristics of patients with Leber congenital amaurosis from the previously unexplored Polish population. Our study expands the mutational spectrum as we report 10 novel variants identified in LCA genes. The fact that the most frequent causes of the disease in the studied group of Polish patients are mutations in one out of three genes that are currently the targets for gene therapy (CEP290, GUCY2D, and RPE65) strongly emphasizes the importance of the molecular background analyses of LCA in Polish patients.

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GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies

Cited by 47 publications

References 37 publications

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Extending the phenotypic spectrum of PRPF8, PRPH2, RP1 and RPGR, and the genotypic spectrum of early-onset severe retinal dystrophy

Novel gene variants in Polish patients with Leber congenital amaurosis (LCA)

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