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

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 phen...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	usher syndrome exogenous retinoids retinal degeneration natural history PCDH15 Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/b6069badb6b14498bff5ec71588e5683
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spelling	oai:doaj.org-article:b6069badb6b14498bff5ec71588e56832021-11-09T12:30:41ZProposed therapy, developed in a Pcdh15-deficient mouse, for progressive loss of vision in human Usher syndrome10.7554/eLife.673612050-084Xe67361https://doaj.org/article/b6069badb6b14498bff5ec71588e56832021-11-01T00:00:00Zhttps://elifesciences.org/articles/67361https://doaj.org/toc/2050-084XUsher 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.Saumil SethnaWadih M ZeinSehar RiazArnaud PJ GieseJulie M SchultzTodd DuncanRobert B HufnagelCarmen C BrewerAndrew J GriffithT Michael RedmondSaima RiazuddinThomas B FriedmanZubair M AhmedeLife Sciences Publications Ltdarticleusher syndromeexogenous retinoidsretinal degenerationnatural historyPCDH15MedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	usher syndrome exogenous retinoids retinal degeneration natural history PCDH15 Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	usher syndrome exogenous retinoids retinal degeneration natural history PCDH15 Medicine R Science Q Biology (General) QH301-705.5 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 Proposed therapy, developed in a Pcdh15-deficient mouse, for progressive loss of vision in human Usher syndrome
description	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.
format	article
author	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
author_facet	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
author_sort	Saumil Sethna
title	Proposed therapy, developed in a Pcdh15-deficient mouse, for progressive loss of vision in human Usher syndrome
title_short	Proposed therapy, developed in a Pcdh15-deficient mouse, for progressive loss of vision in human Usher syndrome
title_full	Proposed therapy, developed in a Pcdh15-deficient mouse, for progressive loss of vision in human Usher syndrome
title_fullStr	Proposed therapy, developed in a Pcdh15-deficient mouse, for progressive loss of vision in human Usher syndrome
title_full_unstemmed	Proposed therapy, developed in a Pcdh15-deficient mouse, for progressive loss of vision in human Usher syndrome
title_sort	proposed therapy, developed in a pcdh15-deficient mouse, for progressive loss of vision in human usher syndrome
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/b6069badb6b14498bff5ec71588e5683
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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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