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

项目概要/摘要 遗传性疾病是失明的主要原因。这些疾病通常是单基因疾病。一些 可能导致早期眼形成的发育缺陷，其他导致感光细胞变性 细胞，而其他可能导致眼前节疾病。从历史上看，它们是根据 临床表型，然后分组为各种疾病实体。视网膜色素变性（RP），一个例子， 视杆-视锥营养不良是遗传性视网膜疾病的最常见形式。它有一个古典的星座 眼部检查中观察到的发现伴随着视杆细胞和视锥细胞的进行性丧失 最终导致疾病晚期失明。在过去的三十年里，许多人的基因基础 例如，已经发现了遗传性视网膜疾病的形式，导致超过270种的鉴定。 视网膜疾病基因已知超过80个基因的突变与RP单独相关。但在 尽管已经取得了巨大的进展，但致病性遗传改变的鉴定可以 仅在50-75%的假定遗传性视网膜疾病患者中发现，即使在全基因组测序后， 测序基于这一事实，推测存在大量未知的眼病基因。 鉴定哺乳动物视网膜中其他眼病基因的一种方法是利用 敲除小鼠技术。敲除小鼠表型分析（KOMP）计划是国际 Mouse Phenotyping Consortium（IMPC）是一组来自世界各地小鼠诊所的科学家， 共同的目标是为小鼠基因组中的每个基因创建单基因敲除小鼠。迄今为止， 已经建立了单基因敲除小鼠，并对约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小鼠生物学项目是美国仅有的三个KOMP/IMPC中心之一， 为KOMP管道产生大量敲除小鼠。小鼠淘汰赛获得全面的 在尸检和组织病理学之前的前四个月内，每个器官系统的表型。 敲除线被注释为几十个特定的眼睛异常，这些异常在手术过程中被仔细记录。 表型分析过程。在敲除小鼠中鉴定眼病基因提供候选眼 与人类相关的疾病基因该提案旨在缩小其余25-50%患者的差距 目前还无法通过基因诊断的遗传性眼病在这个项目中，我们将 确定KOMP鉴定的所有小鼠视网膜疾病基因。此外，我们将这些新的 通过与GTEx数据库的交叉引用， 此外，我们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、Panther Pathway、STRING、Syscilia、CiliaCarta和公开可用的 眼科GWAS。该提案将催化发现并产生基于临床的新假设。 以前与眼病无关的相关途径。

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.