Functional characterization of CEP250 variant identified in nonsyndromic retinitis pigmentosa
Functional characterization of CEP250 variant identified in nonsyndromic retinitis pigmentosa
复制标题
非综合征性色素性视网膜炎中鉴定的 CEP250 变异的功能特征
DOI：
10.1002/humu.23759
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发表时间：
2019-08-01
期刊：
影响因子：
3.9
通讯作者：
Jin, Zi-Bing
中科院分区：
文献类型：
--
作者：
Huang, Xiu-Feng;Xiang, Lue;Jin, Zi-Bing
视网膜色素变性（RP）是遗传性视网膜疾病最常见的表现形式，具有高度的遗传、等位基因和表型异质性。CEP250编码C - Nap1蛋白，并与多种视网膜表型相关。在此，我们报道了在一个患有非综合征性RP的近亲家族中CEP250的一个突变（c.562C>T，p.R188*）的鉴定。为了深入了解CEP250缺陷的分子病理机制以及CEP250变异体在人类中的功能相关性，我们利用一种新的Cep250基因敲入小鼠品系对CEP250变异体进行了功能特性研究。值得注意的是，Cep250的破坏导致视网膜功能严重受损以及视网膜形态发生显著改变。纯合子基因敲入小鼠显示视网膜厚度和视网膜电图（ERG）反应显著降低。这项研究不仅拓宽了与CEP250突变相关的表型谱，而且首次利用新建立的动物模型阐明了CEP250在光感受器中的功能。
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.