GENES UNDERLYING THE ETIOLOGY OF EYE DISEASES

眼部疾病病因的基因

• 批准号: 8171732
• 负责人: GYUNGAH JUN
• 金额: $ 0.99万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171732
• 关键词: 1p36; Affect; Age; Age related macular degeneration; Aging; Blindness; Cataract; Computer Retrieval of Information on Scientific Projects Database; EPHA2 gene; Etiology; Exons; Eye diseases; Family; Funding; Genes; Genetic; Grant; Human; Institution; Lens Fiber; Link; Meta-Analysis; Missense Mutation; Mouse Strains; Mus; Orthologous Gene; Protein Kinase; Reporting; Research; Research Personnel; Resources; SKIV2L gene; Sampling; Source; United States National Institutes of Health; Variant; age related; base; cohort; fiber cell; follow-up; genetic variant; genome-wide; lens; population based; protective effect

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. Age-related cataract is a major cause of blindness worldwide. Although a significant fraction of age-related cataract is heritable, the genetic basis remains to be elucidated. Homozygous deletion of the EPHA2 gene in two independent strains of mice developed progressive cortical cataract. EPHA2 is highly expressed in both human and mouse lens fiber cells and its expression level decreases with aging in mice. The orthologous gene resides on human 1p36 that was previously reported as showing linkage with age-related cortical cataract in a population-based cohort. We sequenced exons of EPHA2 in linked families and identified a new missense mutation, Arg721Gln in the protein kinase domain which significantly alters EPHA2 functions. Common variants in EPHA2 also showed significant association, and rs6678616 was the most significant in meta-analysis. Thus, converging evidence from humans and mice suggests that EPHA2 is important in maintaining lens clarity with increasing age. In addition, we have recently investigated the genetics of age-related macular degeneration (AMD) with a genomewide association analysis on a sample of families enriched for AMD plus follow-up of implicated chromosomal regions on several independent cohorts. In addition to well-known loci affecting AMD, we identified genetic variants in the genes SKIV2L and MYRIP that appear to exert a protective effect.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 与年龄相关的白内障是全世界失明的主要原因。虽然具有重大意义 部分与年龄有关的白内障是可遗传的，遗传基础仍有待确定 阐明了。两个独立品系的小鼠中 EPHA2 基因的纯合缺失导致了进行性皮质白内障。 EPHA2在人和小鼠晶状体纤维细胞中高度表达，并且其表达水平随着小鼠衰老而降低。该直系同源基因位于人类 1p36 上，之前有报道称该基因与基于人群的队列中与年龄相关的皮质白内障存在关联。我们对连锁家族中 EPHA2 的外显子进行了测序，并在蛋白激酶结构域中发现了一个新的错义突变 Arg721Gln，该突变显着改变了 EPHA2 功能。 EPHA2 中的常见变异也显示出显着关联，其中 rs6678616 在荟萃分析中最为显着。因此，来自人类和小鼠的综合证据表明，随着年龄的增长，EPHA2 对于维持晶状体清晰度很重要。此外，我们最近研究了年龄相关性黄斑变性 (AMD) 的遗传学，对富含 AMD 的家族样本进行了全基因组关联分析，并对几个独立队列的相关染色体区域进行了随访。 除了影响 AMD 的众所周知的基因座外，我们还发现了 SKIV2L 和 MYRIP 基因中似乎发挥保护作用的遗传变异。