Mutation in CEP250 Cause Non-Syndromic Retinitis Pigmentosa

Background: Retinitis pigmentosa (RP) is the most common manifestation of inherited retinal diseases that primarily affects photoreceptor function, and is generally exhibited with high degree of genetic, allelic and phenotypic heterogeneity. CEP250 encodes the C-Nap1 protein and has been associated with various retinal phenotypes. Methods: Whole-exome sequencing was performed to identify the genetic defects. We conducted a functional characterization of causative gene in vivo using a novel knockin mouse line. Findings: Here, we report the identification of a mutation (c.562C>T, p.R188X) in the CEP250 gene in a consanguineous family with non-syndromic RP. The truncated protein lead to disruption of the Rootletin domain and loss of the SMC domains and a NEK2-phosphorylation region. Remarkably, the disruption of Cep250 resulted in severe impairment of retinal function and significant retinal morphological alterations. The homozygous knockin mice showed significantly reduced retinal thickness and ERG responses. Immuno- and TUNEL staining revealed retinal cell apoptosis, shortened outer segments and aberrant cilium-specific proteins (GT335 and Rab8). Interpretation: Our findings demonstrate that disruption of Cep250 in mice results in retinal dysfunction, indicating that the Cep250-knockin mouse line may be very useful for future studies on Cep250 containing protein modules and photoreceptor ciliary biology. This study not only broadens the spectrum of phenotypes associated with CEP250 mutations, but also, for the first time, elucidates the function of CEP250 in photoreceptors using a newly established animal model. Funding: This study was supported by the National Natural Science Foundation of China (31771390, 81522014), National Key R&D Program of China (2017YFA0105300, 2017YFB0403700), Zhejiang Provincial Natural Science Foundation of China (LD18H120001), Zhejiang Provincial Key Research and Development Program (2015C03029), 111 project (D16011), Wenzhou Science and Technology Innovation Team Project (C20150004). Declaration of Interest: The authors disclose no potential conflicts of interest. Ethical Approval: Patients were diagnosed by ophthalmic examinations at the Eye Hospital of the Wenzhou Medical University. The study was approved by the ethics committee. Informed consent was obtained from the patients. This study conformed to the tenets of the Declaration of Helsinki.