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Robert Rosencrans, Russell J Amato, Yongdong Zhou, Nicolas G Bazan, Jennifer J. Lentz; Early changes in retinal structures in a mouse model of Usher syndrome . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4638.
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© ARVO (1962-2015); The Authors (2016-present)
Usher syndrome is the leading genetic cause of combined deafness and blindness. Type 1 Usher (Usher 1) is the most severe form of the disease characterized by profound hearing impairment and vestibular dysfunction at birth and the development of retinitis pigmentosa (RP) in early adolescence. Our previously described knock-in mouse model that contains the USH1C c.216G>A mutation responsible for Acadian Usher 1C, exhibits vestibular dysfunction, profound deafness, reduced electroretinograms at all ages tested from 1 month to 12 months of age, and photoreceptor loss by 6 to 12 months of age. The present study extends these findings by demonstrating differences in retinal structure that occur by post-natal day 30, as detected by Spectral Domain Optical Coherence Tomography (SD-OCT). With these data, the natural history of OCT phenotype in Ush1c mutant mice is described from 1 to 6 months of age.
Retinal structures in anesthetized Ush1c c.216G>A mutant (216AA) and control (216GG/GA) littermate mice at various ages were evaluated by SD-OCT image analysis using a 2007 Heidelberg Engineering HRA + OCT Spectralis. Line and volume scans between two and four millimeters superior and inferior to the optic nerve were taken with a minimum 30 images averaged into each slice. Layer thicknesses at positions medial, temporal, and nasal to the optic nerve were analyzed manually using digital calipers. The grader and technician were blinded to genotype. Images in which layers were not clearly resolved were discarded at the discretion of the grader.
SD-OCT image analysis showed significant differences in retinal layer thickness between216AA mutant mice and control littermates as early as 1 month of age. Photoreceptor outer nuclear layer thickness in 216AA mutant mice was significantly reduced at 1 month of age, however, at 3 and 6 months of age, was not significantly different from wild type mice. Photoreceptor inner and outer segment length in 216AA mutant mice was initially significantly longer compared to wild type mice, however, by 6 months of age 216AA photoreceptors were significantly shorter.
SD-OCT analysis revealed structural differences in the retina as early as 1 month of age in Ush1c c.216G>A mutant mice. These data suggest a retinal developmental delay prior to the onset of photoreceptor degeneration and provide insight into the mechanism of retinitis pigmentosa associated with Usher syndrome.
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