USHER SYNDROME, RETINITIS PIGMENTOSA AND GENETIC MUTATIONS IN RHESUS MACAQUES

恒河猴的 USHER 综合征、色素性视网膜炎和基因突变

• 批准号: 7716423
• 负责人: William J Kimberling
• 金额: $ 4.1万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-23 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7716423
• 关键词: Accounting; Affect; Blindness; Computer Retrieval of Information on Scientific Projects Database; Cysteine; Disease; Frequencies; Funding; Gene Mutation; Genes; Genetic; Genetic Screening; Grant; Health Services Research; Hearing; Human; Inherited; Institution; Macaca; Macaca mulatta; Manuscripts; Modeling; Mus; Mutation; Pathologic; Primates; Probability; Property; Proteins; Rate; Recessive Genes; Research; Research Personnel; Resources; Retina; Retinitis Pigmentosa; Rodent; Screening procedure; Sensorineural Hearing Loss; Source; Testing; United States; United States National Institutes of Health; Usher Syndrome; base; insight; prevent; three dimensional structure

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. To develop a primate model of Usher Syndrome by genetic screening. Usher syndrome, a recessive disorder characterized by retinitis pigmentosa (RP) and sensorineural hearing loss, is the leading cause of combined hearing and vision loss in the industrialized world, affecting 25,000-30,000 people in the United States. Mutations in the USH2A gene account for over half of Usher syndrome cases and 25-50% of autosomal recessive RP cases, which affects about 67,000 people in the United States. Disparities in retina function indicate that rodents may not be ideal models for this type of RP. Based on the carrier rate for the average recessive gene, we predict that screening 500 macaques has a 95% probability of detecting a pathologic mutation. We screened for macaque carriers of USH2A mutations because these mutations are a common genetic cause of RP in humans. Based on frequency, differences in physicochemical properties, rarity of the substitution in related proteins, and modeling of possible alterations of the 3 dimensional structure, the best candidate for a pathologic mutation is R878C which adds another cysteine next to the conserved cysteine that forms loop c in the 7th LE domain. A macaque model would provide insights into pathologic mechanisms for retinitis pigmentosa, and may be better suited than mice for testing new treatments that could reduce or prevent inherited blindness. A manuscript describing these findings is currently under review. This research used WNPRC Research Services.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 通过基因筛查开发usher综合征的灵长类动物模型。 Usher综合征是一种以视网膜炎色素（RP）和感觉性听力损失为特征的隐性疾病，是工业化世界中听力和视力丧失的主要原因，影响了美国25,000-30,000人。 USH2A基因中的突变占USHER综合征病例的一半以上，而常染色体隐性RP病例的25-50％影响了美国约67,000人。视网膜功能的差异表明啮齿动物可能不是这种类型的RP的理想模型。 基于平均隐性基因的载体速率，我们预测筛选500猕猴的概率为95％，可以检测病理突变。 我们筛选了USH2A突变的猕猴载体，因为这些突变是人类RP的常见遗传原因。根据频率，物理化学特性的差异，相关蛋白质中取代的罕见性以及3维结构可能改变的建模，病理突变的最佳候选者是R878C，它在7th Le域中循环的保守半胱氨酸旁边增加了另一个半胱氨酸。猕猴模型将提供有关色素性视网膜炎的病理机制的见解，并且可能比小鼠测试可以减少或预防遗传失明的新治疗方法更适合。目前正在审查描述这些发现的手稿。这项研究使用了WNPRC研究服务。