Genetics of Fuchs Corneal Dystrophy

描述（由申请人提供）：Fuchs角膜营养不良（FCD）是一种角膜内皮退行性疾病，其特征是形成绒毛，下层富含胶原的细胞外基质（称为Descemets膜）的突起。平均发病年龄为50岁，患者通常在六七十岁时达到终末期，此时眼膜覆盖了大部分角膜，内皮细胞的离子转运功能严重受损。口蹄疫是一种常见疾病，40岁以上人口中有4%受到影响。尽管这种疾病对健康和社会经济有影响，但对其潜在机制和遗传负荷的了解很少，唯一可用的治疗方法是角膜移植手术。这是首个为期三年的竞争性续期项目，我们将扩展我们之前的临床和基因研究：a)扩大我们对FCD临床表现和进展的理解；B)确定其潜在的遗传原因；c)开始开发FCD突变的体外和体内模型。我们的工作由三个具体目标组成，这些目标汲取了跨学科团队的优势。首先，我们将扩大患者收集并定量记录与已知FCD基因位点相关的家庭进展（包括我们小组在过去一年中发现的两个新基因位点）。其次，利用我们独特的队列，丰富了大型多代家庭，我们将使用传统遗传学工具和外显子捕获结合下一代重测序来识别FCD的新基因。最后，我们将扩展我们最近在迟发性FCD家族中发现的TCF8家族性功能缺失突变，以建立该疾病的体外和体内模型，作为了解其细胞基础的一种手段。这些研究的完成将显著提高对这种常见疾病的遗传基础的理解，为其病理机制提供重要的新见解，并为建立疾病表现和进展率提供关键措施，这将是患者管理和设计新的治疗范例所必需的。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This grant proposal continues to expand our understanding of the clinical presentation of Fuchs corneal dystrophy, and its underlying genetic basis, which will lead to development of better therapeutic models and treatment for a corneal dystrophy that affects 4% of the population over age 40.