Genetics of Fuchs Corneal Dystrophy

Fuchs角膜营养不良（FCD）是角膜内皮的退行性疾病， 影响到40岁以上人口的近4%， 每年在美国进行的移植手术。尽管对健康和社会经济的影响， 疾病，知识的基本机制和遗传负荷是稀疏的，与唯一的 可用的治疗是角膜移植手术。在这次竞争性的更新中，我们将扩大 我们以前的临床和遗传学研究，a）扩大我们对临床的理解， FCD的表现和进展; B）确定其潜在的遗传原因;和c）开始 开发FCD突变的体外和体内模型。我们的工作包括三个具体的 目标是利用跨学科团队的优势。首先，我们将扩大我们的病人 收集并定量记录与已知FCD基因座相关的家族进展 （包括我们小组在过去一年中发现的两个新位点），并调查听力损失 作为FCD的新的潜在内表型。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 结合传统的遗传学工具和外显子捕获，再加上下一代的重新， 测序最后，我们将利用最近开发的敲入小鼠模型， 我们的实验室了解TCF8家族性功能丧失突变的细胞基础， 迟发性FCD家族。这三个目标代表了有价值的临床和遗传的平衡。 分析加上功能实验，旨在解剖分子组成部分， 对角膜内皮生物学至关重要，并了解生物化学和细胞机制 疾病病理学的基础。完成这些研究将大大提高我们的 了解这种常见疾病的遗传基础，提供重要的新见解， 病理机制，并提供建立疾病表现的关键措施， 进展率，这将是必要的患者管理和设计新的 治疗范例

Fuchs corneal dystrophy (FCD) is a degenerative disorder of the corneal endothelium that affects nearly 4% of the population above 40 years of age and accounts for the majority of transplants performed each year in the US. 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. In this competing renewal, 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), and investigate hearing loss as a new potential endophenotype of FCD. 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 re- sequencing. Finally, we will take advantage of the knock-in mouse model developed recently in our laboratory to understand the cellular basis of familial loss of function mutations in TCF8 in late-onset FCD families. These three aims represent a balance of valuable clinical and genetic analyses coupled with functional experiments designed to dissect the molecular components essential to corneal endothelial biology and understand biochemical and cellular mechanisms underlying the disease pathology. Completion of these studies will significantly enhance our 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.