Development of Refractive Errors—What Can We Learn From Inherited Retinal Dystrophies?

Hendriks, Michelle; Verhoeven, Virginie Jm; Buitendijk, Gabriëlle H.S.; Polling, Jan Roelof; Hofman, Albert; Kamermans, Maarten; Huet, Ramon A. van; Klevering, B. Jeroen; Bax, Nathalie M.; Lambertus, Stanley; Klaver, Caroline C W; Hoyng, Carel B.; Oomen, Clasien J.; Zelst-Stams, Wendy A. van; Cremers, Frans P.M.; Plomp, Astrid S.; Schooneveld, Mary J. van; Genderen, Mies M. van; Schuil, J; Boonstra, F. Nienke; Schlingemann, Reinier O.; Bergen, Arthur A. B.; Pierrache, Laurence; Meester-Smoor, Magda A.; Born, L. Ingeborgh van den; Boon, Camiel J F; Pott, Jan Willem R.; Leeuwen, Redmer van; Kroes, Hester Y.; Jong‐Hesse, Yvonne de

doi:10.1016/j.ajo.2017.07.008

Cited by 70 publications

(40 citation statements)

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“…Many of the identified proteins had previously been linked to the development of secondary pathologies (macular degeneration and choroidal neovascularization) in humans, and proteins negatively correlated with ocular refraction across lens groups at 6 h were enriched for genes linked to human photoreceptor dystrophies and mitochondrial disorders [ 66 ]. This finding is consistent with human genetic studies showing a high incidence of refractive errors in individuals with inherited photoreceptor dystrophies [ 75 ] as well as a recent refractive error genome-wide association meta-analyses implicating ‘abnormal photoreceptor inner segment morphology’ as the most significant gene set [ 76 ]. Such changes to photoreceptor dynamics are predicted by Crewther’s Retinal Ion-Driven Fluid Efflux (RIDE) model [ 77 ].…”

Section: Introductionsupporting

confidence: 88%

“…The need for signalling adaptations at the photoreceptor-bipolar level is predicted by our RIDE model [ 77 ] and consistent with pharmacological and gene knockout studies showing that changes to the balance of ON and OFF bipolar signalling can affect post-natal ocular growth and the induction of optically-induced refractive errors [ 38 , 127 – 133 ]. Recent genetic studies have also strongly implicated photoreceptor and bipolar cell signalling in the development of refractive errors in humans [ 75 , 76 ].…”

Section: Discussionmentioning

confidence: 99%

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Short term optical defocus perturbs normal developmental shifts in retina/RPE protein abundance

Riddell

Faou

2018

BMC Dev Biol

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BackgroundMyopia (short-sightedness) affects approximately 1.4 billion people worldwide, and prevalence is increasing. Animal models induced by defocusing lenses show striking similarity with human myopia in terms of morphology and the implicated genetic pathways. Less is known about proteome changes in animals. Thus, the present study aimed to improve understanding of protein pathway responses to lens defocus, with an emphasis on relating expression changes to no lens control development and identifying bidirectional and/or distinct pathways across myopia and hyperopia (long-sightedness) models.ResultsQuantitative label-free proteomics and gene set enrichment analysis (GSEA) were used to examine protein pathway expression in the retina/RPE of chicks following 6 h and 48 h of myopia induction with − 10 dioptre (D) lenses, hyperopia induction with +10D lenses, or normal no lens rearing. Seventy-one pathways linked to cell development and neuronal maturation were differentially enriched between 6 and 48 h in no lens chicks. The majority of these normal developmental changes were disrupted by lens-wear (47 of 71 pathways), however, only 11 pathways displayed distinct expression profiles across the lens conditions. Most notably, negative lens-wear induced up-regulation of proteins involved in ATP-driven ion transport, calcium homeostasis, and GABA signalling between 6 and 48 h, while the same proteins were down-regulated over time in normally developing chicks. Glutamate and bicarbonate/chloride transporters were also down-regulated over time in normally developing chicks, and positive lens-wear inhibited this down-regulation.ConclusionsThe chick retina/RPE proteome undergoes extensive pathway expression shifts during normal development. Most of these pathways are further disrupted by lens-wear. The identified expression patterns suggest close interactions between neurotransmission (as exemplified by increased GABA receptor and synaptic protein expression), cellular ion homeostasis, and associated energy resources during myopia induction. We have also provided novel evidence for changes to SLC-mediated transmembrane transport during hyperopia induction, with potential implications for signalling at the photoreceptor-bipolar synapse. These findings reflect a key role for perturbed neurotransmission and ionic homeostasis in optically-induced refractive errors, and are predicted by our Retinal Ion Driven Efflux (RIDE) model.Electronic supplementary materialThe online version of this article (10.1186/s12861-018-0177-1) contains supplementary material, which is available to authorized users.

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Section: Introductionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Short term optical defocus perturbs normal developmental shifts in retina/RPE protein abundance

Riddell

Faou

2018

BMC Dev Biol

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“…Although the reasons for the association between RPGR mutations and high myopia remain unclear, a recent study analyzing refractive errors in inherited retinal dystrophies has postulated that the transport area between the inner and outer segment (i.e., the location of protein RPGR), is one of the critical sites for refractive error development. 28 Mutations in RP1 and RP2, encoding an outer segment protein and another connecting cilium protein, respectively, have also been linked to high myopia, 29,30 further corroborating this hypothesis. However, not all genes encoding connecting cilium proteins are associated with myopia, and some have been associated with hyperopia (e.g., CEP290 and RPGRIP1), and biallelic mutations in these are generally associated with much more extreme visual loss due to Leber congenital amaurosis.…”

Section: Discussionmentioning

confidence: 70%

The Spectrum of Structural and Functional Abnormalities in Female Carriers of Pathogenic Variants in theRPGRGene

Talib

Schooneveld

Cauwenbergh

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The purpose of this study was to investigate the phenotype and long-term clinical course of female carriers of RPGR mutations.METHODS. This was a retrospective cohort study of 125 heterozygous RPGR mutation carriers from 49 families.RESULTS. Eighty-three heterozygotes were from retinitis pigmentosa (RP) pedigrees, 37 were from cone-/cone-rod dystrophy (COD/CORD) pedigrees, and 5 heterozygotes were from pedigrees with mixed RP/CORD or unknown diagnosis. Mutations were located in exon 1-14 and in ORF15 in 42 of 125 (34%) and 83 of 125 (66%) subjects, respectively. The mean age at the first examination was 34.4 years (range, 2.1 to 86.0 years). The median follow-up time in heterozygotes with longitudinal data (n ¼ 62) was 12.2 years (range, 1.1 to 52.2 years). Retinal pigmentary changes were present in 73 (58%) individuals. Visual symptoms were reported in 51 (40%) cases. Subjects with both symptoms and pigmentary fundus changes were older than the other heterozygotes (P ¼ 0.01) and had thinner foveal outer retinas (P ¼ 0.006). Complete expression of the RP or CORD phenotype was observed in 29 (23%) heterozygotes, although usually in milder forms than in affected male relatives. Best-corrected visual acuity (BCVA) was <20/40 and <20/400 in at least one eye in 45 of 116 (39%) and 11 of 116 (9%) heterozygotes, respectively. Myopia was observed in 74 of 101 (73%) subjects and was associated with lower BCVA (P ¼ 0.006). Increasing age was associated with lower BCVA (P ¼ 0.002) and decreasing visual field size (P ¼ 0.012; I4e isopter).CONCLUSIONS. RPGR mutations lead to a phenotypic spectrum in female carriers, with myopia as a significantly aggravating factor. Complete disease expression is observed in some individuals, who may benefit from future (gene) therapeutic options.

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“…High hyperopia (i.e., refractive error of more than +5.00 D) was present in both siblings. TULP1 ‐associated disease has previously been associated with myopia (den Hollander, Lopez et al., ; den Hollander, van Lith‐Verhoeven et al., ; Hendriks et al., ; Souzeau et al., ) and hyperopia (den Hollander, Lopez et al., ; Khan, Bergmann, Eisenberger, & Bolz, ). However, high hyperopia has only been described in patients with LCA, and is thought to result from impaired emmetropization caused by early‐onset visual impairment (Khan et al., ; Weleber et al., ).…”

Section: Discussionmentioning

confidence: 99%

The identification of a RNA splice variant in TULP1 in two siblings with early‐onset photoreceptor dystrophy

Verbakel

Fadaie

Klevering

et al. 2019

Molec Gen & Gen Med

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Background Early‐onset photoreceptor dystrophies are a major cause of irreversible visual impairment in children and young adults. This clinically heterogeneous group of disorders can be caused by mutations in many genes. Nevertheless, to date, 30%–40% of cases remain genetically unexplained. In view of expanding therapeutic options, it is essential to obtain a molecular diagnosis in these patients as well. In this study, we aimed to identify the genetic cause in two siblings with genetically unexplained retinal disease. Methods Whole exome sequencing was performed to identify the causative variants in two siblings in whom a single pathogenic variant in TULP1 was found previously. Patients were clinically evaluated, including assessment of the medical history, slit‐lamp biomicroscopy, and ophthalmoscopy. In addition, a functional analysis of the putative splice variant in TULP1 was performed using a midigene assay. Results Clinical assessment showed a typical early‐onset photoreceptor dystrophy in both the patients. Whole exome sequencing identified two pathogenic variants in TULP1, a c.1445G>A (p.(Arg482Gln)) missense mutation and an intronic c.718+23G>A variant. Segregation analysis confirmed that both siblings were compound heterozygous for the TULP1 c.718+23G>A and c.1445G>A variants, while the unaffected parents were heterozygous. The midigene assay for the c.718+23G>A variant confirmed an elongation of exon 7 leading to a frameshift. Conclusion Here, we report the first near‐exon RNA splice variant that is not present in a consensus splice site sequence in TULP1, which was found in a compound heterozygous manner with a previously described pathogenic TULP1 variant in two patients with an early‐onset photoreceptor dystrophy. We provide proof of pathogenicity for this splice variant by performing an in vitro midigene splice assay, and highlight the importance of analysis of noncoding regions beyond the noncanonical splice sites in patients with inherited retinal diseases.

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Development of Refractive Errors—What Can We Learn From Inherited Retinal Dystrophies?

Abstract: Refractive errors, in particular myopia, are common in IRD. The bipolar synapse and the inner and outer segments of the photoreceptor may serve as critical sites for myopia development.

Cited by 70 publications

References 39 publications

Short term optical defocus perturbs normal developmental shifts in retina/RPE protein abundance

Short term optical defocus perturbs normal developmental shifts in retina/RPE protein abundance

The Spectrum of Structural and Functional Abnormalities in Female Carriers of Pathogenic Variants in theRPGRGene

The identification of a RNA splice variant in TULP1 in two siblings with early‐onset photoreceptor dystrophy

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