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    Proposed therapy, developed in a Pcdh15-deficient mouse, for progressive loss of vision in human Usher syndrome

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    Author
    Sethna, Saumil
    Zein, Wadih M
    Riaz, Sehar
    Giese, Arnaud Pj
    Schultz, Julie M
    Duncan, Todd
    Hufnagel, Robert B
    Brewer, Carmen C
    Griffith, Andrew J
    Redmond, T Michael
    Riazuddin, Saima
    Friedman, Thomas B
    Ahmed, Zubair M
    Show allShow less

    Date
    2021-11-09
    Journal
    eLife
    Publisher
    eLife Sciences Publications
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.7554/eLife.67361
    Abstract
    Usher syndrome type I (USH1) is characterized by deafness, vestibular areflexia, and progressive retinal degeneration. The protein-truncating p.Arg245* founder variant of PCDH15 (USH1F) has an ~2% carrier frequency amongst Ashkenazi Jews accounts for ~60% of their USH1 cases. Here, longitudinal phenotyping in 13 USH1F individuals revealed progressive retinal degeneration, leading to severe vision loss with macular atrophy by the sixth decade. Half of the affected individuals were legally blind by their mid-50s. The mouse Pcdh15R250X variant is equivalent to human p.Arg245*. Homozygous Pcdh15R250X mice also have visual deficits and aberrant light-dependent translocation of the phototransduction cascade proteins, arrestin, and transducin. Retinal pigment epithelium (RPE)-specific retinoid cycle proteins, RPE65 and CRALBP, were also reduced in Pcdh15R250X mice, indicating a dual role for protocadherin-15 in photoreceptors and RPE. Exogenous 9-cis retinal improved ERG amplitudes in Pcdh15R250X mice, suggesting a basis for a clinical trial of FDA-approved retinoids to preserve vision in USH1F patients.
    Keyword
    PCDH15
    cell biology
    exogenous retinoids
    human
    medicine
    mouse
    natural history
    retinal degeneration
    usher syndrome
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/17126
    ae974a485f413a2113503eed53cd6c53
    10.7554/eLife.67361
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