USH2A Gene Mutations in Rabbits Lead to Progressive Retinal Degeneration and Hearing Loss.

Area of Science:

• Genetics
• Ophthalmology
• Auditory Science

Background:

• Mutations in the USH2A gene are a primary cause of Usher Syndrome (USH).
• Over 30% of USH cases involve frameshift mutations in exon 13 of the USH2A gene.
• A clinically relevant animal model for USH2A-related vision loss has been lacking.

Purpose of the Study:

• To establish a rabbit model with a USH2A frameshift mutation equivalent to human exon 13.
• To investigate the resulting auditory and visual phenotypes in the developed animal model.

Main Methods:

• CRISPR/Cas9 gene editing was used to introduce a USH2A mutation in rabbit embryos.
• Mutant rabbits underwent comprehensive functional and morphological analyses.
• Tests included auditory brainstem responses, electroretinography, OCT, fundus imaging, and histology.

Main Results:

• Mutant rabbits showed early signs of retinal pigment epithelium damage (hyper-autofluorescence, OCT hyper-reflectivity).
• Moderate to severe hearing loss was detected via auditory brainstem response.
• Progressive vision loss, including rod and cone dysfunction, was observed and confirmed histopathologically.

Conclusions:

• Disrupting the USH2A gene in rabbits successfully induces hearing loss and progressive photoreceptor degeneration.
• This rabbit model accurately mimics the clinical presentation of USH2A-related Usher Syndrome.
• This study establishes the first mammalian model of USH2 with a retinitis pigmentosa phenotype.