Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina
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 albes...
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2021
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Online Access: | http://dx.doi.org/10.7554/elife.71473 https://cdn.elifesciences.org/articles/71473/elife-71473-v2.pdf https://cdn.elifesciences.org/articles/71473/elife-71473-v2.xml https://elifesciences.org/articles/71473 |
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crelifesciences:10.7554/elife.71473 2024-09-30T14:38:56+00:00 Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina Schlegel, Domino K Ramkumar, Srinivasagan von Lintig, Johannes Neuhauss, Stephan CF Schweizerische Nationalfonds National Eye Institute National Eye Institute Robert und Rosa Pulfer Stiftung 2021 http://dx.doi.org/10.7554/elife.71473 https://cdn.elifesciences.org/articles/71473/elife-71473-v2.pdf https://cdn.elifesciences.org/articles/71473/elife-71473-v2.xml https://elifesciences.org/articles/71473 en eng eLife Sciences Publications, Ltd http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/ eLife volume 10 ISSN 2050-084X journal-article 2021 crelifesciences https://doi.org/10.7554/elife.71473 2024-09-17T04:53:16Z 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. Article in Journal/Newspaper Newfoundland eLife eLife 10 |
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eLife |
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crelifesciences |
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English |
description |
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. |
author2 |
Schweizerische Nationalfonds National Eye Institute National Eye Institute Robert und Rosa Pulfer Stiftung |
format |
Article in Journal/Newspaper |
author |
Schlegel, Domino K Ramkumar, Srinivasagan von Lintig, Johannes Neuhauss, Stephan CF |
spellingShingle |
Schlegel, Domino K Ramkumar, Srinivasagan von Lintig, Johannes Neuhauss, Stephan CF Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina |
author_facet |
Schlegel, Domino K Ramkumar, Srinivasagan von Lintig, Johannes Neuhauss, Stephan CF |
author_sort |
Schlegel, Domino K |
title |
Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina |
title_short |
Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina |
title_full |
Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina |
title_fullStr |
Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina |
title_full_unstemmed |
Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina |
title_sort |
disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina |
publisher |
eLife Sciences Publications, Ltd |
publishDate |
2021 |
url |
http://dx.doi.org/10.7554/elife.71473 https://cdn.elifesciences.org/articles/71473/elife-71473-v2.pdf https://cdn.elifesciences.org/articles/71473/elife-71473-v2.xml https://elifesciences.org/articles/71473 |
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Newfoundland |
genre_facet |
Newfoundland |
op_source |
eLife volume 10 ISSN 2050-084X |
op_rights |
http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/ |
op_doi |
https://doi.org/10.7554/elife.71473 |
container_title |
eLife |
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10 |
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1811641514872274944 |