中国人群中视网膜色素变性的研究

项目名称： 中国人群中视网膜色素变性的研究

项目编号： No.31471196

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 王慧

作者单位： 杭州师范大学

项目金额： 85万元

中文摘要： 视网膜色素变性(Retinitis Pigmentosa, RP)是视网膜疾病中的最常见一种疾病，在世界范围内的患病率约为1/4000，患者最初表现为夜盲，视野范围逐渐缩小，最终导致失明。视网膜色素变性具有高度的异质性，目前为止已发现有52个 基因上的突变会导致该疾病，而这52个基因仅能解释大约50%视网膜色素变性患者的致病原因，因而对于视网膜色素变性疾病还有很大的研究空间。申请人将对433名中国视网膜色素变性患者进行以下的分析研究： A.利用外显子富集结合二代测序的方法对视网膜色素变性患者进行已知基因上突变的检测，建立中国人群视网膜色素变性的突变频谱； B.建立视网膜色素变性患者临床表型与基因型的相关性，提高诊断的准确率； C.寻找视网膜色素变性的新基因，初步探索致病机理。

中文关键词： 遗传病；致病基因；基因突变；分子诊断

英文摘要： The main goal of this proposal is to identify multiple novel genes underlying Retinitis Pigmentosa (RP) and get a better idea of the mutation spectrum in Chinese RP patients based on large data set. RP is highly genetic heterogeneous with the molecular basis for about 50% of RP patients remain unknown. To achieve comprehensive and accurate diagnosis for this disease, it is essential to identify the remaining disease genes. Furthermore, subsequent studies of these novel disease genes will lead to new insights of disease mechanisms as well as for developing new diagnosis and treatment methods. Retinitis Pigmentosa is the most common form of retinal degeneration and affects 1 in 4,000 people around the world. Patients with RP lose vision because rods and cones die throughout the retina. The age of onset of RP can vary from birth (LCA), to infancy (juvenile RP) and early adulthood (adult onset RP). Consistent with these highly variable clinical phenotypes, the inheritance of RP is also complex, including autosomal dominant (ad), autosomal recessive (ar), and X-linked recessive (xr). In addition, digenic (controlled by two genes) and mitochondrial forms have also been described. Different retinal dystrophies often share many common features and many known RP disease genes, such as CRX, CRB1, IMPDH1, RDH12, RPE65, TULP1, and SPATA7, have also been linked to other clinical appearances, including LCA and Cone Rod Dystrophy. Similar phenomena have been observed with many known RP genes. These observations indicate that the mechanisms underlying RP are often shared among many forms of retinal diseases, including neurologic and developmental disorders, intellectual disabilities, hearing impairment, short stature and other skeletal anomalies, and kidney disease. Indeed, several genes that are associated with syndromic diseases have recently been linked to nonsyndromic RP, such as CEP290, Ush2A, and NPHP5. Due to its clinically and genetically heterogeneous nature, it is difficult to identify compounds that can treat all RP patients effectively. Translational medicine that relies on molecular biology, pharmacogenomics, and genetics offers an attractive alternative. To achieve this goal, we have established a large collection of RP patient families, including 18 families with at least 9 affected members in each family. In addition, about 100 smaller families with two or more affected members have also been collected. To systematically identify multiple novel RP disease genes in this collection, we propose to use a combination of regional and whole exome sequencing (WES), bioinformatics, statistics, and functional studies.

英文关键词： retinitis pigmentosa;capture sequencing;next-generation sequencing;mutation spectrum;mutation detection