USH2A gene mutations in rabbits lead to progressive retinal degeneration and hearing loss

Abstract

Mutations in USH2A gene are responsible for the greatest proportion of hearing and vision loss among individuals with Usher Syndrome (USH) and for autosomal recessive non-syndromic retinitis pigmentosa. Mutations on USH2A exon 13 account for more than 35% of the disease causing USH2A variants including the most prevalence point mutation, c.2299delG, a frameshift mutation. The lack of a clinically relevant animal model has been a bottleneck for the development of therapeutics for USH2A related vision loss. Using CRSPR/Cas9 technology, this study establishes a rabbit line carrying an USH2A frameshift mutation on exon12 (equivalent to human USH2A Exon 13) as a novel mammalian animal model of USH2A. The bi-allelic mutant rabbits exhibit hyper reflective signals in FAF indicating RPE damage and OCT changes indicating photoreceptor degeneration as early as 4 months of age. ERG signals of both rod and cone function were reduced in the USH2A mutant rabbits starting from 7 months old and further decreased at 15-22 months old, indicating progressive retinal photoreceptor degeneration, which is further confirmed by retinal histopathology examination. ABR examination showed moderate to server hearing loss in the USH2A mutant rabbits. These results indicated that disruption of USH2A gene in rabbits is sufficient to induce hearing loss and progressive photoreceptor degeneration. To our knowledge, this is the first mammalian animal model of USH2 which closely recapitulates the phenotype of retinitis pigmentosa in human patients. This study supports the use of rabbits as a clinically relevant animal model to understand the pathogenesis and to develop novel therapeutics for Usher Syndrome.