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，影响近4%的40岁以上人群，占美国每年进行的移植的大多数。尽管这种疾病对健康和社会经济产生了影响，但对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。在这 为了竞争更新，我们将扩展我们先前的临床和遗传研究，以a）扩展我们对FCD临床表现和进展的理解; B）确定其潜在的遗传原因;和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，这些目标来自跨学科团队的优势。首先，我们将扩大我们的患者样本量，并定量记录与已知FCD基因座相关的家庭的进展（包括我们小组在过去一年中发现的两个新基因座），并将听力损失作为FCD的一种新的潜在内在表型进行研究。第二，利用我们的独特群组，其富集了大型多代家族，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的组合来鉴定FCD的novl基因。最后，我们将利用我们实验室最近开发的基因敲入小鼠模型来了解晚发型FCD家族中TCF 8功能缺失突变的细胞基础。这三个目标代表了有价值的临床和遗传分析与功能实验的平衡，这些实验旨在解剖角膜内皮生物学所必需的分子组分，并了解疾病病理学的生化和细胞机制。这些研究的完成将大大提高我们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，这对患者管理和设计新的治疗模式是必要的。

DESCRIPTION (provided by applicant): 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 novl 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.