Proposed therapy, developed in a <i>Pcdh15</i>-deficient mouse, for progressive loss of vision in human Usher syndrome.

Abstract

Usher syndrome type I (USH1) is characterized by deafness, vestibular areflexia, and progressive retinal degeneration. The protein-truncating p.Arg245* founder variant of <i>PCDH15</i> (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 <i>Pcdh15^R250X</i> variant is equivalent to human p.Arg245*. Homozygous <i>Pcdh15^R250X</i> 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 <i>Pcdh15^R250X</i> mice, indicating a dual role for protocadherin-15 in photoreceptors and RPE. Exogenous 9-<i>cis</i> retinal improved ERG amplitudes in <i>Pcdh15^R250X</i> mice, suggesting a basis for a clinical trial of FDA-approved retinoids to preserve vision in USH1F patients.