Homozygous Knockout of Cep250 Leads to a Relatively Late-Onset Retinal Degeneration and Sensorineural Hearing Loss in Mice

Purpose: Usher syndrome (USH) is the most common syndromic inherited retinal disease, causing retinitis pigmentosa and sensorineural hearing loss. We reported previ-ously that a nonsense mutation in the centrosome-associated protein CEP250 gene (encoding C-Nap1) causes atypical USH in patients of Iranian Jewish origin. To better characterize CEP250, we aimed to generate and study a knockout (KO) mouse model for Cep250.Methods: Mice heterozygous for a "knockout-first" Cep250 construct were generated and bred with Cre recombinase mice to generate the null allele and produce homozy-gous Cep250 KO mice. Retinal function was evaluated by full-field electroretinography (ffERG) at variable ages, and retinal structure changes were examined using histological analysis. Hearing thresholds were detected using auditory brainstem response (ABR) at the age of 20 months.Results: The Cep250 KO mouse model was generated by activating a construct harbor-ing a deletion of exons 6 and 7. At 6 months, the ffERG was normal, but it decreased gradually with age. For both photopic and scotopic ffERG responses, very low ampli-tudes were evident at 20 months. Histological analysis confirmed late-onset retinal degeneration. ABR tests illustrated that hearing threshold significantly increased at the age of 20 months.Conclusions: Although most USH animal models have normal retinal function and structure, the Cep250 KO mouse model shows both retinal degeneration and hearing loss with a relatively late age of onset. This model may shed more light on CEP250- associated retinal and hearing deficits and represents an efficient platform for the devel-opment of treatment modalities for USH.ranslational Relevance: Our study demonstrates better understanding of Cep250- associated retinal and hearing disease in a mouse model and may help in developing more efficient gene therapy modalities.