常染色体隐性遗传RP新致病基因鉴定及初步功能研究

视网膜色素变性（RP）是最常见的遗传性致盲眼病，近半数原因不明，确定致病基因及其突变是RP防治的前提。我们在遗传资源采集和全外显子组测序分析的基础上，分析了903个RP家系先证者，筛选出了至少5个可能的常染色体隐性遗传RP（arRP）新候选致病基因。本项目拟在此基础上，通过人和鼠眼及全身组织表达分析、斑马鱼基因敲低和小鼠基因敲除模型研究，确定这些基因的全身表达特点及眼组织中主要表达的部位及细胞类型，分析EXTL2、DACT2、TMED5、M***和N*****等5个基因纯合缺失的表型特点、累及视网膜的主要细胞及锥杆细胞功能改变，结合临床病例扩展数据判定这些基因缺失突变的致病性，并初步了解其基本功能。项目涉及的实验技术，已成功用于我们最近完成的其它遗传性眼病的新致病基因研究。本项目的研究结果将有助于扩展arRP发病原因认识，对本病的预防和治疗有理论价值和潜在应用前景。

Retinitis pigmentosa (RP) is the most common inherited disease causing blindness. Genetic defects in about half of the families are awaited to be identified even though tremendous progress in the identification of causative genes has been made in the past 29 years. Based on collection of families with hereditary eye diseases and whole exome sequencing on their genomic DNA, homozygous loss of function mutations in at least 5 novel candidate genes were detected in patients with autosomal recessive RP on analysis of probands from 903 families with RP, including EXTL2, DACT2, TMED5, M***, and N*****. In this study, tissue and cell specific expression of these genes will be further characterized in human donor tissues and mouse tissues. The pathogenesis and potential functional impact of these genes will be studied by examing the phenotypic and functional changes in knockdown zebrafish models as well as in knock-out mouse models, in which the experimental methods have been successfully applied in our recent published works on identification of novel genes responsible for Leber congenital amaurosis or early onset high myopia. Clinical data from patients with mutations combined with experimental data obtained from above-mentioned studies would enable us to characterize the role of mull mutations in these genes. The results from this program will expand our knowledge of genes responsible for arRP and finally advance the prevention and treatment of the blindness disease.