Functional characterization of CEP250 variant identified in nonsyndromic retinitis pigmentosa

Retinitis pigmentosa (RP) is the most common manifestation of inherited retinal diseases with high degree of genetic, allelic, and phenotypic heterogeneity. CEP250 encodes the C‐Nap1 protein and has been associated with various retinal phenotypes. Here, we report the identification of a mutation (c....

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Published in:	Human mutation 2019-08, Vol.40 (8), p.1039-1045, Article humu.23759
Main Authors:	Huang, Xiu‐Feng, Xiang, Lue, Fang, Xiao‐Long, Liu, Wei‐Qin, Zhuang, You‐Yuan, Chen, Zhen‐Ji, Shen, Ren‐Juan, Cheng, Wan, Han, Ru‐Yi, Zheng, Si‐Si, Chen, Xue‐Jiao, Liu, Xiaoling, Jin, Zi‐Bing
Format:	Article
Language:	eng
Subjects:	Animal models Animals Autoantigens - genetics Autoantigens - metabolism Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism CEP250 cilia Codon, Nonsense Consanguinity Disease Models, Animal Electroretinograms Exome Sequencing - methods Female Gene Knock-In Techniques Humans knockin mice Mice Mutation nonsyndromic RP Pedigree Phenotype Phenotypes Photoreceptors Polymorphism, Single Nucleotide Retina retinal dysfunction Retinitis Retinitis pigmentosa Retinitis Pigmentosa - genetics Retinitis Pigmentosa - metabolism
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Summary:	Retinitis pigmentosa (RP) is the most common manifestation of inherited retinal diseases with high degree of genetic, allelic, and phenotypic heterogeneity. CEP250 encodes the C‐Nap1 protein and has been associated with various retinal phenotypes. Here, we report the identification of a mutation (c.562C>T, p.R188*) in the CEP250 in a consanguineous family with nonsyndromic RP. To gain insights into the molecular pathomechanism underlying CEP250 defects and the functional relevance of CEP250 variants in humans, we conducted a functional characterization of CEP250 variant using a novel Cep250 knockin mouse line. 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. 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. The disruption of Cep250 resulted in severe impairment of retinal function and significant retinal morphological alterations. For the first time, this study investigated the function of CEP250 in photoreceptors using a newly established animal model.
ISSN:	1059-7794 1098-1004