Proposed therapy, developed in a Pcdh15-deficient mouse, for progressive loss of vision in human Usher syndrome
Saumil Sethna,
Wadih M Zein,
Sehar Riaz,
Arnaud PJ Giese,
Julie M Schultz,
Todd Duncan,
Robert B Hufnagel,
Carmen C Brewer,
Andrew J Griffith,
T Michael Redmond,
Saima Riazuddin,
Thomas B Friedman,
Zubair M Ahmed
Affiliations
Saumil Sethna
Department of Otorhinolaryngology - Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, United States
Wadih M Zein
Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, United States
Sehar Riaz
Department of Otorhinolaryngology - Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, United States; National Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
Arnaud PJ Giese
Department of Otorhinolaryngology - Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, United States
Julie M Schultz
Laboratory of Molecular Genetics, National Institute of Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, United States
Todd Duncan
Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, United States
Robert B Hufnagel
Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, United States
Carmen C Brewer
Otolaryngology Branch, National Institute of Deafness and Other Communication Disorders, Bethesda, United States
Andrew J Griffith
Otolaryngology Branch, National Institute of Deafness and Other Communication Disorders, Bethesda, United States
T Michael Redmond
Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, United States
Saima Riazuddin
Department of Otorhinolaryngology - Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, United States
Laboratory of Molecular Genetics, National Institute of Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, United States
Department of Otorhinolaryngology - Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, United States; Departments of Ophthalmology and Visual Sciences, University of Maryland School of Medicine, Baltimore, United States; Departments of Molecular Biology and Biochemistry, University of Maryland School of Medicine, Baltimore, United States
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.
