Interrogation and Interpretation of Common Fund Data Sets to Identify Novel Ocular Disease Genes

项目摘要/摘要 遗传性疾病是导致失明的主要原因。这些疾病是典型的单基因疾病。一些人 可能会导致眼睛形成早期的发育缺陷，其他可能会导致感光细胞退化 细胞，而其他细胞则可能导致眼前节疾病。从历史上看，它们都是根据 临床表型，然后分组为各种疾病实体。视网膜色素变性(RP)，一例 视杆细胞营养不良，是最常见的遗传性视网膜疾病。它有一个古典的星座 伴随视杆和视锥感光细胞进行性丧失的眼科检查结果 最终导致疾病晚期失明。在过去的三十年里，许多 例如，各种形式的遗传性视网膜疾病已经被发现，导致了270多个 视网膜疾病基因。已知有超过80个基因的突变仅与RP有关。但是，在 尽管已经取得了巨大的进步，但对致病基因改变的鉴定可以 仅在50%-75%的假定遗传性视网膜疾病患者中发现，即使在全基因组之后也是如此 测序。基于这一事实，可以推测存在大量未知的眼病基因。 在哺乳动物视网膜中识别其他眼病基因的一种方法是利用 击倒鼠标技术。基因敲除小鼠表型(KOMP)计划是国际 小鼠表型鉴定联盟(IMPC)，一个由来自世界各地老鼠诊所的科学家组成的小组 共同的目标是为小鼠基因组中的每一个基因创造单基因敲除小鼠。到目前为止，已有超过7,000人 已经建立了单基因敲除小鼠，并对小鼠体内约24,000个蛋白质编码基因进行了表型分析 小鼠基因组。加州大学戴维斯分校的老鼠生物学项目是美国仅有的三个KOMP/IMPC中心之一， 为KOMP管道产生大量的基因敲除小鼠。鼠标击倒获得全面 在尸检和组织病理学之前的生命的前四个月，每个器官系统的表型。 对数十种特定的眼睛异常情况进行了注释，这些异常情况在 表型鉴定过程。在基因敲除小鼠中识别眼部疾病基因提供候选眼睛 与人类相关的疾病基因。这项提议旨在缩小剩余25%-50%的患者的差距 患有目前无法从基因上诊断的假定遗传性眼病。在这个项目中，我们将 确定KOMP确定的所有小鼠视网膜疾病基因。此外，我们还将把这些小说联系起来 通过与GTEx数据库的交叉引用，小鼠眼病基因与人类的相关性，也 由共同基金提供支持。此外，我们还将深入分析新基因的特定细胞生物学， 通过文献检索、基因本体论、黑豹路径、字符串、Syscilia、CiliaCarta和公开可用 眼科疾病。这一建议将催化发现并产生基于临床的新假说 之前未涉及眼部疾病的相关通路。

Project Summary/Abstract Inherited diseases are a major source of blindness. These diseases are typically single-gene disorders. Some may cause developmental defects in early eye formation, others cause the degeneration of photoreceptor cells, while others may cause anterior segment disease. Historically they have been classified based on the clinical phenotype and then grouped into various disease entities. Retinitis pigmentosa (RP), an example of a rod-cone dystrophy, is the most common form of inherited retinal disease. It has a constellation of classical findings observed on eye examination accompanied by progressive loss of rod and then cone photoreceptors leading to eventual blindness in late stages of the disease. In the past three decades the genetic basis of many forms of inherited retinal diseases, for example, have been discovered leading to the identification of over 270 retinal disease genes. Mutations of over 80 genes are known to be associated with RP alone. However, in spite of the tremendous progress that has been made, the identification of the causative genetic alteration can be identified in only 50-75% of patients with presumed inherited retinal disease, even after whole genome sequencing. Based on this fact, it is presumed that significant numbers of unknown ocular disease genes exist. One approach to identify additional ocular disease genes in the mammalian retina is to take advantage of knockout mouse technology. The Knockout Mouse Phenotyping (KOMP) program is part of the International Mouse Phenotyping Consortium (IMPC), a group of scientists from mouse clinics around the world with the common goal of creating single gene knockout mice for every gene in the mouse genome. To date, over 7,000 single gene knockout mice have been created and phenotyped of the ~24,000 protein coding genes in the mouse genome. The UC Davis Mouse Biology Program is one of just three KOMP/IMPC centers in the US and generates a large number of knockout mice for the KOMP pipeline. Mouse knockouts receive comprehensive phenotyping in every organ system in the first four months of life prior to necropsy and histopathology. Knockout lines are annotated for dozens of specific eye abnormalities which are carefully documented during the phenotyping process. Identification of ocular disease genes in knockout mice provides candidate eye disease genes relevant in people. This proposal seeks to close the gap on the remaining 25-50% of patients with presumed inherited ocular diseases that currently cannot be genetically diagnosed. In this project we will identify all mouse retinal disease genes identified by the KOMP. In addition, we will correlate these novel mouse ocular disease genes for human relevance by cross referencing with the GTEx data base, also supported by the Common Fund. Furthermore, we will deeply analyze the specific cell biology of novel genes, by literature search, Gene Ontology, Panther Pathway, STRING, Syscilia, CiliaCarta, and publicly available ophthalmic GWAS. This proposal will catalyze discoveries and generate novel hypotheses based on clinically relevant pathways previously unimplicated in eye disease.