CEP78基因突变引起视网膜变性的遗传机制及干预研究

Usher syndrome, characterized by sensorineural hearing loss and retinal degeneration, is a type of syndromic inherited retinal diseases. It is also a remarkable cause for blindness and deafness in the Chinese population. To date, as a monogenic disease, Usher syndrome has 13 reported disease causing genes. Our group has recently identified and reported CEP78 as a novel disease causative gene for Usher syndrome. However, the role of CEP78 mutations in the pathogenesis of Usher syndrome remains unclear. In this study, we aim to investigate the association between CEP78 mutations and Usher syndrome according to the following three aspects: 1) Build CEP78-/- mice model, analyze its retinal phenotypes, and reveal the molecular mechanism of retinal dysfunctions caused by CEP78 mutations; 2) Construct rAAV vector carrying CEP78 mRNA, and evaluate the efficiency and safety of gene therapy targeting CEP78 gene; 3) Construct genetic and clinical resource libraries of IRD patients, identify their disease causative mutations using targeted next-generation sequencing based platform, and analyze their genotype-phenotype correlations. Taken together, our study aims to investigate the role of CEP78 mutations in the genetic and mechanistic pathogenesis of IRD, and provide novel insights into the clinical treatment for IRD patients.

Usher综合征是遗传性视网膜变性疾病（IRD）的一种，以感音神经性耳聋和视网膜变性为主要疾病表现，严重危害我国国民健康。Usher综合征是单基因病，目前已知的致病基因就有13个。CEP78基因是由本课题组率先发现并报道的一种特殊类型Usher综合征的致病基因，然其致病机制尚不明确。本研究拟从以下几个方面对CEP78基因缺陷与视网膜变性的关联展开深入研究：1）构建CEP78-/-小鼠模型，揭示CEP78基因缺陷引起的小鼠视网膜疾病表型及感光细胞变性的分子机制；2）构建带有CEP78基因的rAAV载体，在CEP78-/-小鼠模型中，评估靶向CEP78的基因治疗的有效性和安全性；3）设计并构建基于NGS的靶基因捕获测序平台，在IRD患者中高效筛查CEP78基因突变，明确CEP78基因突变的遗传致病意义。本项目旨在深入研究CEP78基因缺陷引起视网膜变性的遗传背景和机制，并为基因治疗提供新思路。

遗传性视网膜变性疾病（IRD）是一种遗传性致盲性眼病，严重危害我国国民健康。CEP78基因是由本课题组率先发现并报道的IRD的致病基因，然其致病机制尚不明确。本研究从以下几个方面对CEP78基因缺陷与视网膜变性的关联展开深入研究：1）构建了CEP78-/-小鼠模型，揭示了CEP78基因缺陷引起的小鼠视网膜疾病表型，发现了CEP78基因缺陷引起感光细胞变性的机制，CEP78缺失将破坏感光细胞纤毛的结构和功能；2）构建了带有CEP78基因的rAAV载体，在CEP78-/-小鼠模型中评估了靶向CEP78的基因治疗的有效性和安全性；3）设计并构建了基于高通量二代测序的IRD分子诊断平台，在IRD患者中高效筛查了CEP78基因突变，明确了CEP78基因突变的遗传致病意义；4）发现雄性CEP78-/-小鼠不育，且存在精子数量和形态的异常，雄性CEP78-/-小鼠精子鞭毛微管排列及头部形成异常；5）明确了CEP78基因缺失致病的分子机制，CEP78能够与CP110蛋白及纤毛蛋白IFT20、TTC21A产生直接相互作用，调节中心粒的延长；6）找到了IRD发病相关的两个新致病基因——IFT52和CRB2，并对其致病机制进行了分析和研究。本项目深入研究了CEP78基因缺陷引起视网膜变性的遗传背景和机制，为IRD的分子诊断和基因治疗提供新思路。