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Dissecting the role of EYS in retinal degeneration: clinical and molecular aspects and its implications for future therapy.

ABSTRACT: Mutations in the EYS gene are one of the major causes of autosomal recessive retinitis pigmentosa. EYS-retinopathy presents a severe clinical phenotype, and patients currently have no therapeutic options. The progress in personalised medicine and gene and cell therapies hold promise for treating this degenerative disease. However, lack of understanding and incomplete comprehension of disease's mechanism and the role of EYS in the healthy retina are critical limitations for the translation of current technical advances into real therapeutic possibilities. This review recapitulates the present knowledge about EYS-retinopathies, their clinical presentations and proposed genotype-phenotype correlations. Molecular details of the gene and the protein, mainly based on animal model data, are analysed. The proposed cellular localisation and roles of this large multi-domain protein are detailed. Future therapeutic approaches for EYS-retinopathies are discussed.

SUBMITTER: Garcia-Delgado AB

PROVIDER: S-EPMC8127272 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Dissecting the role of EYS in retinal degeneration: clinical and molecular aspects and its implications for future therapy.

Garcia-Delgado Ana B AB Valdes-Sanchez Lourdes L Morillo-Sanchez Maria Jose MJ Ponte-Zuñiga Beatriz B Diaz-Corrales Francisco J FJ de la Cerda Berta B

Orphanet journal of rare diseases 20210517 1

Mutations in the EYS gene are one of the major causes of autosomal recessive retinitis pigmentosa. EYS-retinopathy presents a severe clinical phenotype, and patients currently have no therapeutic options. The progress in personalised medicine and gene and cell therapies hold promise for treating this degenerative disease. However, lack of understanding and incomplete comprehension of disease's mechanism and the role of EYS in the healthy retina are critical limitations for the translation of cur ...[more]

PMID: 34001227

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Project description:Age-related macular degeneration (AMD), the leading cause of blindness in elderly populations, involves the loss of central vision due to progressive dysfunction of the retinal pigment epithelium (RPE) and subsequent loss of light-sensing photoreceptors. While age is a key risk factor, not every aged individual develops AMD. Thus, the critical question is what specific cellular changes tip the balance from healthy aging to disease. To distinguish between changes associated with aging and AMD, we compared the RPE proteome in human eye bank tissue from nondiseased donors during aging (n = 50, 29-91 years) and in donors with AMD (n = 36) compared to age-matched donors without disease (n = 28). Proteins from RPE cells were separated on two-dimensional gels, analyzed for content, and identified using mass spectrometry. A total of 58 proteins displayed significantly altered content with either aging or AMD. Proteins involved in metabolism, protein turnover, stress response, and cell death were altered with both aging and AMD. However, the direction of change was predominantly opposite. With aging, we detected an overall decrease in metabolism and reductions in stress-associated proteins, proteases, and chaperones. With AMD, we observed upregulation of metabolic proteins involved in glycolysis, TCA, and fatty acid metabolism, with a concurrent decline in oxidative phosphorylation, suggesting a reprogramming of energy utilization. Additionally, we detected upregulation of proteins involved in the stress response and protein turnover. Predicted upstream regulators also showed divergent results, with inhibition of inflammation and immune response with aging and activation of these processes with AMD. Our results support the idea that AMD is not simply advanced aging but rather the culmination of perturbed protein homeostasis, defective bioenergetics, and increased oxidative stress within the aging RPE, exacerbated by environmental factors and the genetic background of an individual.

Project description:ImportanceThe PROM1 gene, commonly associated with cone-rod dystrophies, may have dominant or recessive phenotypes that influence disease onset and severity.ObjectiveTo characterize the clinical phenotype and molecular genetic variations in patients with PROM1 variants.Design, setting, and participantsThis case-series study was conducted at 2 specialist retinal genetics clinics and examined 19 consecutively enrolled patients with PROM1-related retinal degeneration. Data were collected and analyzed from May 2018 to December 2018.Main outcomes and measuresResults of ophthalmic examination, retinal imaging, and molecular genetic analysis by next-generation sequencing.ResultsOf 19 patients, 13 (68%) were women, and age ranged from 11 to 70 years. All patients presented with central visual loss, with or without photophobia. Individuals with recessive variants commonly had severe loss of visual acuity by their 20s, whereas the dominant variant was associated with a milder phenotype, with most patients retaining good vision into late adulthood. The recessive cases were associated with a panretinal dystrophy of cone-rod phenotype with early macular involvement, whereas the dominant variants were associated with a cone-rod phenotype that was restricted to the macula with predominantly cone dysfunction. Next-generation sequencing identified 3 novel and 9 previously reported variants in PROM1. Recessive mutations included 6 truncating variants (3 nonsense and 3 frameshift), 4 splice site variants, and 1 missense variant. All 6 dominant variants were associated with a c.1117C>T missense variant. The variants were distributed throughout the PROM1 genomic sequence with no specific clustering on protein domains.Conclusions and relevanceIn this case-series study, PROM1 recessive variants were associated with early-onset, severe panretinal degeneration. The similar phenotypes observed in patients with homozygous missense variants and splice site variants compared with similarly aged patients with truncating variants suggests that all recessive variants have a null (or loss of function close to null) outcome on PROM1 function. In contrast, the dominant missense cases were associated with a milder, cone-driven phenotype, suggesting that the dominant disease is preferentially associated with cones. This has implications for the development of treatments for this severely blinding disease, and adeno-associated viral vector-based gene therapy and optogenetics could become successful treatment options.

Dataset Information

Dissecting the role of EYS in retinal degeneration: clinical and molecular aspects and its implications for future therapy.

Publications

Dissecting the role of EYS in retinal degeneration: clinical and molecular aspects and its implications for future therapy.

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