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

  1. Domino K Schlegel
  2. Srinivasagan Ramkumar
  3. Johannes von Lintig
  4. Stephan CF Neuhauss  Is a corresponding author
  1. University of Zurich, Switzerland
  2. Case Western Reserve University, United States
  3. Case Western Reserve, United States

Abstract

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.

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All data generated or analysed during this study are included in the manuscript. Source data files for all figures have been provided.

Article and author information

Author details

  1. Domino K Schlegel

    University of Zurich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  2. Srinivasagan Ramkumar

    Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Johannes von Lintig

    Case Western Reserve, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Stephan CF Neuhauss

    Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland
    For correspondence
    stephan.neuhauss@mls.uzh.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9615-480X

Funding

Schweizerische Nationalfonds (31003A_173083)

  • Stephan CF Neuhauss

National Eye Institute (EY028121)

  • Johannes von Lintig

National Eye Institute (EY020551)

  • Johannes von Lintig

Robert und Rosa Pulfer Stiftung

  • Domino K Schlegel

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Holding and experimental permits have been granted by the Zurich cantonal veterinary office (TV4206)

Copyright

© 2021, Schlegel et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Domino K Schlegel
  2. Srinivasagan Ramkumar
  3. Johannes von Lintig
  4. Stephan CF Neuhauss
(2021)
Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina
eLife 10:e71473.
https://doi.org/10.7554/eLife.71473

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https://doi.org/10.7554/eLife.71473