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

Alaa Abu-Diab, Prakadeeswari Gopalakrishnan, Chen Matsevich, Marije de Jong, Alexey Obolensky, Ayat Khalaileh, Manar Salameh, Ayala Ejzenberg, Menachem Gross, Eyal Banin, Dror Sharon, Samer Khateb*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Purpose: Usher syndrome (USH) is the most common syndromic inherited retinal disease, causing retinitis pigmentosa and sensorineural hearing loss. We reported previously 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 homozygous 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 harboring 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 amplitudes 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 CEP250associated retinal and hearing deficits and represents an efficient platform for the development of treatment modalities for USH. Translational Relevance: Our study demonstrates better understanding of Cep250associated retinal and hearing disease in a mouse model and may help in developing more efficient gene therapy modalities.

Original languageEnglish
Article number3
JournalTranslational Vision Science and Technology
Volume12
Issue number3
DOIs
StatePublished - 1 Mar 2023

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Keywords

  • CEP250
  • hearing loss
  • knockout
  • retinal degeneration
  • Usher syndrome

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