RPE and Choroid Mechanisms Underlying Ocular Growth and Myopia

Zhang, Yan; Wildsoet, Christine F.

doi:10.1016/bs.pmbts.2015.06.014

Cited by 91 publications

(84 citation statements)

References 99 publications

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“…The increased eye size is restricted to the posterior, retinal portion, leaving the anterior segment essentially unchanged. The posterior portion is enclosed by the RPE, and numerous studies point to the interaction between RPE and the surrounding sclera to be necessary for control of eye growth [44][45][46][47]. However the mechanism by which the eye becomes enlarged is not simply loss of RPE function.…”

Section: Discussionmentioning

confidence: 99%

The nanophthalmos protein TMEM98 inhibits MYRF self-cleavage and is required for eye size specification

et al. 2020

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The precise control of eye size is essential for normal vision. TMEM98 is a highly conserved and widely expressed gene which appears to be involved in eye size regulation. Mutations in human TMEM98 are found in patients with nanophthalmos (very small eyes) and variants near the gene are associated in population studies with myopia and increased eye size. As complete loss of function mutations in mouse Tmem98 result in perinatal lethality, we produced mice deficient for Tmem98 in the retinal pigment epithelium (RPE), where Tmem98 is highly expressed. These mice have greatly enlarged eyes that are very fragile with very thin retinas, compressed choroid and thin sclera. To gain insight into the mechanism of action we used a proximity labelling approach to discover interacting proteins and identified MYRF as an interacting partner. Mutations of MYRF are also associated with nanophthalmos. The protein is an endoplasmic reticulum-tethered transcription factor which undergoes autoproteolytic cleavage to liberate the N-terminal part which then translocates to the nucleus where it acts as a transcription factor. We find that TMEM98 inhibits the self-cleavage of MYRF, in a novel regulatory mechanism. In RPE lacking TMEM98, MYRF is ectopically activated and abnormally localised to the nuclei. Our findings highlight the importance of the interplay between TMEM98 and MYRF in determining the size of the eye.

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Section: Discussionmentioning

confidence: 99%

The nanophthalmos protein TMEM98 inhibits MYRF self-cleavage and is required for eye size specification

et al. 2020

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“…RDH5 is best known for its role in the regeneration of 11-cis retinal in the visual cycle, but the enzyme has also been reported to be capable of producing retinoids suitable for retinoic acid signaling 76,77 . Evidence from animal models implicates retinoic acid in eye growth regulation 12 , and retinal all-trans retinoic acid levels are elevated in a guinea pig model of myopia 78 . Thus the same haplotype, which has risen to substantial frequencies in some populations (0.38 minor haplotype frequency in South Asians and 0.19 in Europeans https://www.ncbi.nlm.nih.gov/projects/SNP/), may dampen retinoic acid signaling during eye development and growth, and later contribute to chronic photoreceptor dysfunction in older adults.…”

Section: Discussionmentioning

confidence: 98%

Ocular disease mechanisms elucidated by genetics of human fetal retinal pigment epithelium gene expression

Liu

Calton

Benchorin

et al. 2018

Preprint

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The eye is an intricate organ with limited representation in large-scale functional genomics datasets. The retinal pigment epithelium (RPE) serves vital roles in ocular development and retinal homeostasis. We interrogated the genetics of gene expression of cultured human fetal RPE (fRPE) cells under two metabolic conditions. Genes with disproportionately high fRPE expression are enriched for genes related to inherited ocular diseases. Variants near these fRPE-selective genes explain a larger fraction of risk for both age-related macular degeneration (AMD) and myopia than variants near genes enriched in 53 other human tissues.Increased mitochondrial oxidation of glutamine by fRPE promoted expression of lipid synthesis genes implicated in AMD. Expression and splice quantitative trait loci (e/sQTL) analysis revealed shared and metabolic condition-specific loci of each type and several eQTL not previously described in any tissue. Fine mapping of fRPE e/sQTL across AMD and myopia genome-wide association data suggests new candidate genes, and mechanisms by which the same common variant of RDH5 contributes to both increased AMD risk and decreased myopia risk. Our study highlights the unique transcriptomic characteristics of fRPE and provides a resource to connect e/sQTL in a critical ocular cell type to monogenic and complex eye disorders.3The importance of vision to humans and the accessibility of the eye to examination have motivated the characterization of more than one thousand genetic conditions involving ocular phenotypes 1 . Among these, numerous monogenic diseases exhibit significant inter-and intra-familial phenotypic variability 2-7 . Imbalance in allelic expression of a handful of causative genes has been documented 8 , but common genetic variants responsible for such effects remain to be discovered.Complementing our knowledge of numerous monogenic ocular disorders, recent genome-wide association studies (GWAS) 9 have identified hundreds of independent loci associated with polygenic ocular phenotypes such as age-related macular degeneration (AMD), the leading cause of blindness in elderly individuals in developed countries 10,11 , and myopia, the most common type of refractive error worldwide and an increasingly common cause of blindness 12-14 . Despite the rapid success of GWAS in mapping novel ocular disease susceptibility loci, the functional mechanisms underlying these associations are often obscure.Connecting changes in molecular functions such as gene expression and splicing with specific GWAS genomic variants has aided the elucidation of functional mechanisms. Non-coding variants account for a preponderance of the most significant GWAS loci 15,16 , and most expression quantitative trait loci (eQTL) map to non-coding variants 17 . Thousands of eQTL have been found in a variety of human tissues 18 , but ocular celltypes are underrepresented among eQTL maps across diverse tissues, and no systematic search for eQTL has so far been described for any cell type in the human eye.The retinal pigment epithelium ...

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“…Phase 2: In diabetic patients with longer duration of disease, the long‐term metabolic abnormalities caused sustained damage of the choroidal vascular cells, occlusion, distortion and local microaneurysm of the choroid capillary, drusen‐like precipitation of the Bruch membrane, atrophy of the choroid, emergence of neovascularization and, finally, DC (Zhu & Wallman ; Kim et al. ; Zhang & Wildsoet ).…”

Section: Discussionmentioning

confidence: 99%

“…Study has shown that at this stage, there was vascular distortion and formation of sinus-like structure between the choroid lobules, which further aggravated the hypoxia and oedema of the choroid, resulting in the increase of CT (Tavares et al 2017). Phase 2: In diabetic patients with longer duration of disease, the long-term metabolic abnormalities caused sustained damage of the choroidal vascular cells, occlusion, distortion and local microaneurysm of the choroid capillary, drusen-like precipitation of the Bruch membrane, atrophy of the choroid, emergence of neovascularization and, finally, DC (Zhu & Wallman 2009;Kim et al 2013;Zhang & Wildsoet 2015).…”

Section: The Role Duration May Plays In the Posterior Pole Choroid Thmentioning

confidence: 99%

Change in peripapillary and macular choroidal thickness change in children with type 1 diabetes mellitus without visual impairment or diabetic retinopathy

Jia

Wang

et al. 2019

Acta Ophthalmologica

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Purpose To study the characteristics of choroid thickness (CT) of the optic disc and macula in children with type 1 diabetes mellitus (T1DM) without visual impairment and diabetic retinopathy (DR) and analyse associated factors. Methods A square area of 6 × 6 mm around the centre of the optic disc and macula was scanned. The indices analysed mainly included CT at the macular centre (1 mm), and temporal, superior, nasal or inferior aspect of the inner ring (1–3 mm) and outer ring of (3–6 mm) optic disc and macula. Independent risk factors were analysed using multifactor linear regression. Results A total of 44 children with T1DM and 48 healthy subjects were enrolled. The diabetic group showed significant increase in the inferior inner ring of parapapillary CT (100.99 ± 30.42 μm versus 89.41 ± 34.00 μm, p = 0.04) and nasal outer ring of parapapillary CT (157.02 ± 47.35 μm versus 131.15 ± 35.17 μm, p = 0.01) as compared to those values in the healthy controls. Spherical equivalent refraction and family history of hypertension are independent factors of both peripappillary choroid thickness (PPCT) and macular choroid thickness (PMCT). Spherical equivalent refraction (p = 0.01) and serum cholesterol (p = 0.03) were independent factors of the inferior inner ring of parapapillary CT, whereas family history of hypertension was an independent factor of the nasal outer ring of parapapillary CT (p = 0.001). Conclusion In children with diabetes without DR or visual impairment, the CT increase in nasal outer ring of parapapillary (PPNO) and the inferior inner ring of parapapillary (PPII) may be the characteristic pre‐DR alteration at the early stage of DM. For children with higher serum cholesterol and family history of hypertension, the change of the nasal outer ring of parapapillary CT and the inferior inner ring of parapapillary CT may be more advanced.

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RPE and Choroid Mechanisms Underlying Ocular Growth and Myopia

Cited by 91 publications

References 99 publications

The nanophthalmos protein TMEM98 inhibits MYRF self-cleavage and is required for eye size specification

The nanophthalmos protein TMEM98 inhibits MYRF self-cleavage and is required for eye size specification

Ocular disease mechanisms elucidated by genetics of human fetal retinal pigment epithelium gene expression

Change in peripapillary and macular choroidal thickness change in children with type 1 diabetes mellitus without visual impairment or diabetic retinopathy

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