Genetics of Fuchs Corneal Dystrophy

Fuchs角膜营养不良（FCD）是一种角膜内皮的退行性疾病 其特征在于形成牙胶，下面的胶原蛋白丰富的突起 细胞外基质称为后弹力膜。平均发病年龄为50岁， 患者通常在60岁和70岁时达到终末期疾病， 覆盖了大部分角膜，内皮细胞的离子转运功能严重受损 暴露了FCD是一种常见的疾病，4%的人口年龄超过40岁 影响。尽管这种疾病对健康和社会经济产生了影响， 潜在的机制和遗传负荷是稀疏的，唯一可用的治疗方法是 角膜移植手术这是第一个竞争性的三年奖，在 我们将扩展我们以前的临床和遗传研究，以a）扩大我们的 了解FCD的临床表现和进展; B）确定其 潜在的遗传原因;和c）开始开发FCD的体外和体内模型 突变。我们的工作包括三个具体目标，这些目标借鉴了 跨学科团队首先，我们将扩大我们的病人收集和定量 在与已知FCD基因座（包括两个新基因座）相关的家族中记录进展 我们的团队在过去的一年中发现了这一点）。第二，利用我们独特的群体优势， 这是丰富的大，多代家庭，我们将确定新的基因， FCD使用传统遗传学工具和外显子捕获的组合， 代重排序。最后，我们将扩展我们最近发现的家庭损失 在晚发型FCD家族中TCF 8的功能突变，以在体外和体内产生 作为理解其细胞基础的一种手段。完成这些 研究将大大提高对这种共同的遗传基础的理解。 疾病，提供重要的新的见解，其病理机制，并提供关键的 确定疾病表现和进展率的措施， 这对于患者管理和新型治疗范例的设计是必要的。

Fuchs corneal dystrophy (FCD) is a degenerative disorder of the corneal endothelium characterized by the formation of guttae, protrusions of the underlying collagen-rich extracellular matrix known as Descemets membrane. The average age of onset is 50, and patients typically reach end stage disease in their 60's and 70's, by which time guttae cover most of the cornea and ion transport functions of the endothelium are severely compromised. FCD is a common condition, with 4% of the population over age 40 affected. Despite the health and socioeconomic impact of the disorder, knowledge of the underlying mechanism and genetic load is sparse, with the only available treatment being corneal transplant surgery. This is the first competing renewal of a three year award, in which we will extend our previous clinical and genetic studies to a) expand our understanding of the clinical presentation and progression of FCD; b) identify its underlying genetic causes; and c) begin developing in vitro and in vivo models for FCD mutations. Our work consists of three specific aims that draw from the strengths of an interdisciplinary team. First, we will expand our patient collection and quantitatively document progression in families linked to known FCD loci (including two novel loci uncovered by our group in the past year). Second, taking advantage of our unique cohort, which is enriched for large, multigenerational families, we will identify novel genes for FCD using a combination of traditional genetics tools and exon capture coupled to next generation resequencing. Finally, we will extend on our recent discovery of familial loss of function mutations in TCF8 in late-onset FCD families, to generate in vitro and in vivo models of the disorder as a means of understanding its cellular basis. Completion of these studies will enhance significantly the understanding of the genetic basis of this common disorder, offer important new insights into its pathomechanism, and provide critical measures for establishing disease presentation and progression rates, which will be necessary for patient management and for the design of novel therapeutic paradigms.