Proposed therapy, developed in a Pcdh15-deficient mouse, for progressive loss of vision in human Usher syndrome
Author
Sethna, SaumilZein, 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
Date
2021-11-09Journal
eLifePublisher
eLife Sciences PublicationsType
Article
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Show full item recordAbstract
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
PCDH15cell biology
exogenous retinoids
human
medicine
mouse
natural history
retinal degeneration
usher syndrome
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http://hdl.handle.net/10713/17126ae974a485f413a2113503eed53cd6c53
10.7554/eLife.67361
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