Genetics of Fuchs Corneal Dystrophy

产品说明：富克斯角膜营养不良（FCD）是一种退行性疾病，其特征在于滴状物的增殖，滴状物是支持角膜内皮的富含胶原的细胞外基质的微观突起。FCD的初始阶段显示这些滴状物的数量逐渐增加，而终末期疾病另外表现出内皮的功能缺陷，其导致水的流入和角膜基质的严重混浊。如何与这种内皮功能障碍的滴仍然是未知的。大约4%的40岁或以上的人受到FCD的影响。晚期疾病的唯一有效治疗方法是角膜移植手术，FCD现在是这种手术的最常见原因。编码胶原蛋白VIII亚基的COL 8A 2基因突变与罕见的儿童期发病形式FCD明确相关。COL 8A 2的突变是否也涉及常见的成人发病形式的疾病尚不清楚。我们计划对成人型FCD进行如下研究：1）我们最近将成人型FCD的第一个位点定位在染色体13 pTel-q12.13区间，最大LOD得分为3.91和3.80。我们计划完善这张图谱并找出突变基因。2)我们对另外3个成人发病FCD大家族的全基因组连锁分析显示，他们每个人都与18 q21的同一位点连锁，在85%的连锁率下，组合多点LOD得分为5.94。目前的疾病间隔包含28个候选人，我们建议通过序列分析和SNP单倍型关联的间隔更详细的映射筛选基因候选人，通过缩小间隔来识别基因。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。这将有助于提高Fuchs角膜营养不良的早期诊断和非手术治疗的发展。

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.