Rod and Cone Photoreceptor Function in Patients with Cone Dystrophy

2004 ◽  
Vol 45 (1) ◽  
pp. 275 ◽  
Author(s):  
Karen Holopigian ◽  
Vivienne C. Greenstein ◽  
William Seiple ◽  
Donald C. Hood ◽  
Ronald E. Carr
Keyword(s):  
Cone Dystrophy ◽  
Cone Photoreceptor

Functional consequences of progressive cone dystrophy-associated mutations in the human cone photoreceptor cyclic nucleotide-gated channel CNGA3 subunit

2005 ◽  
Vol 289 (1) ◽  
pp. C187-C198 ◽  
Author(s):  
Chunming Liu ◽  
Michael D. Varnum
Keyword(s):  
Patch Clamp ◽  
Cyclic Nucleotide ◽  
Fluorescent Protein ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Cone Dystrophy ◽  
Cone Photoreceptor ◽  
Patch Clamp Recording ◽  
Functional Consequences ◽  
Heteromeric Channels

Progressive cone dystrophies are a genetically heterogeneous group of disorders characterized by early deterioration of visual acuity and color vision, together with psychophysical and electrophysiological evidence of abnormal cone function and cone degeneration. Recently, three mutations in the gene encoding the CNGA3 subunit of cone photoreceptor cyclic nucleotide-gated (CNG) channels have been linked to progressive cone dystrophy in humans. To investigate the functional consequences of these mutations, we expressed mutant human CNGA3 subunits in Xenopus oocytes, alone or together with human CNGB3, and studied these channels using patch-clamp recording. Compared with wild-type channels, homomeric and heteromeric channels containing CNGA3-N471S or CNGA3-R563H subunits exhibited an increase in apparent affinity for cGMP and an increase in the relative agonist efficacy of cAMP compared with cGMP. In contrast, R277C subunits did not form functional homomeric or heteromeric channels. Cell surface expression levels, determined using confocal microscopy of green fluorescent protein-tagged subunits and patch-clamp recording, were significantly reduced for both R563H and R277C but unchanged for N471S. Overall, these results suggest that the plasma membrane localization and gating properties of cone CNG channels are altered by progressive cone dystrophy-associated mutations, providing evidence that supports the pathogenicity of these mutations.

scholarly journals Optical Coherence Tomography Findings in Unilateral Peripheral Cone Dysfunction Syndrome: A Case Report

2019 ◽  
Author(s):  
Tetsuya Hasegawa ◽  
Soichi Tetsuka ◽  
Aya Yamaguchi ◽  
Chieko Kobashi ◽  
Tomomi Sato ◽  
...  
Keyword(s):  
Optical Coherence Tomography ◽  
Visual Field ◽  
Amacrine Cells ◽  
Photoreceptor Cells ◽  
Horizontal Cells ◽  
Cone Dystrophy ◽  
Optical Coherence ◽  
Cone Photoreceptor ◽  
Cone Dysfunction ◽  
The Right

Abstract Introduction: To report a case of unilateral peripheral cone dysfunction syndrome and evaluate associated clinicopathological changes using swept-source optical coherence tomography (SS-OCT). Case Presentation: A 39-year-old Japanese woman reported a visual field defect of 2-years duration in the right eye. The patient underwent visual field testing, full-field electroretinography (ff-ERG), SS-OCT, and a routine ophthalmologic examination. The best-corrected visual acuity was 20/20 bilaterally. The funduscopy examination was normal bilaterally. Visual field testing showed a relative paracentral scotoma in the right eye. SS-OCT scans showed an unclear interdigitation zone (IZ) throughout the posterior pole except for the foveal zone in the right eye. SS-OCT macular analysis showed thinning of the ganglion cell layer (GCL) and inner plexiform layer (IPL) corresponding to the region of the IZ defect. ff-ERG showed almost normal flash ERGs and normal rod responses bilaterally. The cone response and flicker ERG were decreased markedly only in the right eye. Conclusion: To the best of our knowledge, this is the first case report of unilateral peripheral cone dysfunction syndrome in which SS-OCT showed pathological changes in the GCL and IPL. The OCT findings corresponded well to the ERG changes and visual field abnormality. Because foveal cone photoreceptor cells are connected in a one-to-one correspondence to retinal ganglion cells without connection to the horizontal cells or amacrine cells, the GCL and IPL were not present in the fovea. Based on this analysis, we speculated that the primary lesion of peripheral cone dysfunction syndrome is not in the cone photoreceptor cells but in the horizontal cells and/or amacrine cells. The clinicopathological changes in the ganglion cells and cone photoreceptor cells might be the subsequent pathologies in the horizontal cells in peripheral cone dysfunction syndrome. Keywords: Cone dystrophy; Ganglion cell complex; Swept-source optical coherence tomography; Peripheral cone dysfunction syndrome; Peripheral cone dystrophy.

scholarly journals Analysis of Early Cone Dysfunction in an In Vivo Model of Rod-Cone Dystrophy

2020 ◽  
Vol 21 (17) ◽  
pp. 6055 ◽  
Author(s):  
Mark Hassall ◽  
Michelle McClements ◽  
Alun Barnard ◽  
Maria Patrício ◽  
Sher Aslam ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
Photoreceptor Cells ◽  
Cell Loss ◽  
Cone Dystrophy ◽  
Cone Photoreceptor ◽  
Cone Cell ◽  
Secondary Degeneration ◽  
Cone Dysfunction ◽  
Cone Function

Retinitis pigmentosa (RP) is a generic term for a group of genetic diseases characterized by loss of rod and cone photoreceptor cells. Although the genetic causes of RP frequently only affect the rod photoreceptor cells, cone photoreceptors become stressed in the absence of rods and undergo a secondary degeneration. Changes in the gene expression profile of cone photoreceptor cells are likely to occur prior to observable physiological changes. To this end, we sought to achieve greater understanding of the changes in cone photoreceptor cells early in the degeneration process of the Rho−/− mouse model. To account for gene expression changes attributed to loss of cone photoreceptor cells, we normalized PCR in the remaining number of cones to a cone cell reporter (OPN1-GFP). Gene expression profiles of key components involved in the cone phototransduction cascade were correlated with tests of retinal cone function prior to cell loss. A significant downregulation of the photoreceptor transcription factor Crx was observed, which preceded a significant downregulation in cone opsin transcripts that coincided with declining cone function. Our data add to the growing understanding of molecular changes that occur prior to cone dysfunction in a model of rod-cone dystrophy. It is of interest that gene supplementation of CRX by adeno-associated viral vector delivery prior to cone cell loss did not prevent cone photoreceptor degeneration in this mouse model.

scholarly journals Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Domino K Schlegel ◽  
Srinivasagan Ramkumar ◽  
Johannes von Lintig ◽  
Stephan CF Neuhauss
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Cone Dystrophy ◽  
Rod Photoreceptor ◽  
Cone Photoreceptor ◽  
Specific Expression ◽  
Retinoid Metabolism ◽  
Light Stimuli ◽  
Cell Type Specific ◽  
Retinal Thinning

The RLBP1 gene encodes the 36 kDa cellular retinaldehyde binding protein, CRALBP, a soluble retinoid carrier, in the visual cycle of the eyes. Mutations in RLBP1 are associated with recessively inherited clinical phenotypes, including Bothnia dystrophy, retinitis pigmentosa, retinitis punctata albescens, fundus albipunctatus, and Newfoundland rod-cone dystrophy. However, the etiology of these retinal disorders is not well understood. Here, we generated homologous zebrafish models to bridge this knowledge gap. Duplication of the rlbp1 gene in zebrafish and cell-specific expression of the paralogs rlbp1a in the retinal pigment epithelium and rlbp1b in Müller glial cells allowed us to create intrinsically cell type-specific knockout fish lines. Using rlbp1a and rlbp1b single and double mutants, we investigated the pathological effects on visual function. Our analyses revealed that rlbp1a was essential for cone photoreceptor function and chromophore metabolism in the fish eyes. rlbp1a mutant fish displayed reduced chromophore levels and attenuated cone photoreceptor responses to light stimuli. They accumulated 11-cis and all-trans-retinyl esters which displayed as enlarged lipid droplets in the RPE reminiscent of the subretinal yellow-white lesions in patients with RLBP1 mutations. During aging, these fish developed retinal thinning and cone and rod photoreceptor dystrophy. In contrast, rlbp1b mutants did not display impaired vision. The double mutant essentially replicated the phenotype of the rlbp1a single mutant. Together, our study showed that the rlbp1a zebrafish mutant recapitulated many features of human blinding diseases caused by RLBP1 mutations and provided novel insights into the pathways for chromophore regeneration of cone photoreceptors.

scholarly journals Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina

2021 ◽  
Author(s):  
Domino K. Schlegel ◽  
Srinivasagan Ramkumar ◽  
Johannes von Lintig ◽  
Stephan C.F. Neuhauss
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Cone Dystrophy ◽  
Rod Photoreceptor ◽  
Cone Photoreceptor ◽  
Specific Expression ◽  
Retinoid Metabolism ◽  
Light Stimuli ◽  
Cell Type Specific ◽  
Retinal Thinning

The RLBP1 gene encodes the 36 kDa cellular retinaldehyde binding protein, CRALBP, a soluble retinoid carrier, in the visual cycle of the eyes. Mutations in RLBP1 are associated with recessively inherited clinical phenotypes, including Bothnia dystrophy, retinitis pigmentosa, retinitis punctata albescens, fundus albipunctatus, and Newfoundland rod-cone dystrophy. However, the etiology of these retinal disorders is not well understood. Here, we generated homologous zebrafish models to bridge this knowledge gap. Duplication of the rlbp1 gene in zebrafish and cell-specific expression of the paralogs rlbp1a in the retinal pigment epithelium and rlbp1b in Mueller glial cells allowed us to create intrinsically cell type-specific knockout fish lines. Using rlbp1a and rlbp1b single and double mutants, we investigated the pathological effects on visual function. Our analyses revealed that rlbp1a was essential for cone photoreceptor function and chromophore metabolism in the fish eyes. rlbp1a mutant fish displayed reduced chromophore levels and attenuated cone photoreceptor responses to light stimuli. They accumulated 11-cis and all-trans-retinyl esters which displayed as enlarged lipid droplets in the RPE reminiscent of the subretinal yellow-white lesions in patients with RLBP1 mutations. During aging, these fish developed retinal thinning and cone and rod photoreceptor dystrophy. In contrast, rlbp1b mutants did not display impaired vision. The double mutant essentially replicated the phenotype of the rlbp1a single mutant. Together, our study showed that the rlbp1a zebrafish mutant recapitulated many features of human blinding diseases caused by RLBP1 mutations and provided novel insights into the pathways for chromophore regeneration of cone photoreceptors.

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