Rs1h -/y exon 3-del rat model of X-linked retinoschisis with early onset and rapid phenotype is rescued by RS1 supplementation.

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  • Additional Information
    • Source:
      Publisher: Nature Publishing Group Country of Publication: England NLM ID: 9421525 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5462 (Electronic) Linking ISSN: 09697128 NLM ISO Abbreviation: Gene Ther Subsets: MEDLINE
    • Publication Information:
      Publication: London : Nature Publishing Group
      Original Publication: Houndmills, Basingstoke, Hampshire, UK : Macmillan Press Ltd., c1994-
    • Subject Terms:
      Cell Adhesion Molecules*/genetics ; Eye Proteins*/genetics ; Eye Proteins*/metabolism ; Retinoschisis*/genetics ; Retinoschisis*/pathology ; Retinoschisis*/therapy; Animals ; Dietary Supplements ; Electroretinography ; Exons/genetics ; Humans ; Phenotype ; Rats ; Retina/metabolism
    • Abstract:
      Animal models of X-linked juvenile retinoschisis (XLRS) are valuable tools for understanding basic biochemical function of retinoschisin (RS1) protein and to investigate outcomes of preclinical efficacy and toxicity studies. In order to work with an eye larger than mouse, we generated and characterized an Rs1h -/y knockout rat model created by removing exon 3. This rat model expresses no normal RS1 protein. The model shares features of an early onset and more severe phenotype of human XLRS. The morphologic pathology includes schisis cavities at postnatal day 15 (p15), photoreceptors that are misplaced into the subretinal space and OPL, and a reduction of photoreceptor cell numbers by p21. By 6 mo age only 1-3 rows of photoreceptors nuclei remain, and the inner/outer segment layers and the OPL shows major changes. Electroretinogram recordings show functional loss with considerable reduction of both the a-wave and b-wave by p28, indicating early age loss and dysfunction of photoreceptors. The ratio of b-/a-wave amplitudes indicates impaired synaptic transmission to bipolar cells in addition. Supplementing the Rs1h -/y exon3-del retina with normal human RS1 protein using AAV8-RS1 delivery improved the retinal structure. This Rs1h -/y rat model provides a further tool to explore underlying mechanisms of XLRS pathology and to evaluate therapeutic intervention for the XLRS condition.
      (© 2021. The Author(s).)
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    • Grant Information:
      Z99 EY999999 United States ImNIH Intramural NIH HHS
    • Accession Number:
      0 (Cell Adhesion Molecules)
      0 (Eye Proteins)
      0 (RS1 protein, human)
    • Publication Date:
      Date Created: 20210922 Date Completed: 20220819 Latest Revision: 20220912
    • Publication Date:
      20240829
    • Accession Number:
      PMC8938309
    • Accession Number:
      10.1038/s41434-021-00290-6
    • Accession Number:
      34548657