Genetics of Fuchs Corneal Dystrophy

描述：Fuchs角膜营养不良（FCD）是一种退行性疾病，其特征是guttes增生，guttes是支持角膜内皮的富含胶原的细胞外基质的微观突起。FCD的初始阶段表现为这些绒毛的数量逐渐增加，而终末期疾病还表现为内皮细胞的功能缺陷，导致水的流入和角膜基质的严重混浊。肠管与内皮功能障碍的关系尚不清楚。40岁或以上的人中约有4%患有口蹄疫。对终末期疾病唯一有效的治疗方法是角膜移植手术，而FCD现在是这种手术最常见的原因。编码胶原蛋白VIII亚基的COL8A2基因突变与一种罕见的儿童发病形式的FCD有明确的联系。COL8A2的突变是否也参与了常见的成人发病形式的疾病尚不清楚。我们计划对成年发病FCD进行如下研究：1)我们最近将成年发病FCD的第一个位点定位在染色体13pTel-q12.13区间，最大LOD评分为3.91和3.80。我们计划完善这张图谱并确定突变基因。2)我们对另外3个成年发病FCD大家族的全基因组连锁分析显示，每个家族在18q21位点都有相同的连锁，在85%的外显率下，多点LOD总分为5.94。目前的疾病间隔包含28个候选；我们建议通过序列分析筛选候选基因，并通过SNP单倍型关联对间隔进行更详细的定位，从而缩小间隔来识别该基因。我们的长期目标是确定成人发病FCD的潜在基因。最终，了解这些基因的身份将为疾病机制提供重要的见解。这应该有助于改善早期诊断和发展的非手术治疗的富氏角膜营养不良。

DESCRIPTION: Fuchs corneal dystrophy (FCD) is a degenerative disorder characterized by the proliferation of guttae, which are microscopic protrusions of the collagen-rich extracellular matrix that supports the corneal endothelium. Initial stages of FCD show progressively increasing numbers of these guttae, while end stage disease exhibits, in addition, functional defects in the endothelium that cause an influx of water and severe clouding of the corneal stroma. How the guttae relate to this endothelial dysfunction remains unknown. About 4% of those who are 40 or older are affected by FCD. The only effective treatment for end stage disease is corneal transplant surgery, and FCD is now the most common reason for such surgery. Mutations in the COL8A2 gene, which encodes a subunit of collagen VIII, have been definitively associated with a rare childhood-onset form of FCD. Whether mutations in COL8A2 are also involved in the common adult-onset forms of the disease is less clear. We plan to investigate adult-onset FCD as follows: 1) We have recently mapped the first locus for adult-onset FCD to the chromosome 13pTel-q12.13 interval, with a maximum LOD scores of 3.91 and 3.80. We plan to refine this map and identify the mutant gene. 2) Our genome-wide linkage analysis of 3 additional large families with adult-onset FCD has revealed that each of them is linked to the same locus at 18q21, with a combined multi-point LOD score of 5.94 at 85% penetrance. The current disease interval contains 28 candidates; we propose to identify the gene by narrowing the interval by screening gene candidates by sequence analysis and more detailed mapping of the interval by SNP haplotype association. Our long term goal is to identify the genes underlying adult-onset FCD. Ultimately, knowing the identity of these genes will provide important insights into disease mechanisms. This should contribute towards improved early diagnosis and the development of non-surgical treatments for Fuchs Corneal Dystrophy.