Genetics of Fuchs Corneal Dystrophy

福克斯角膜营养不良的遗传学

基本信息

批准号：
7344707
负责人：
John D Gottsch
金额：
$ 40.18万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7344707
关键词：
13p Address Adult Affect Age Age of Onset Alleles Candidate Disease Gene Childhood Chromosome Mapping Chromosome inversion Chromosomes Chromosomes, Human, Pair 13 Clinic Code Collagen Collection Cornea Corneal Endothelium Corneal Stroma Corneal dystrophy Cytogenetic Analysis Defect Degenerative Disorder Descemet&apos s membrane Development Developmental Gene Diagnosis Disease Disease Marker Early Diagnosis Employee Strikes Endothelium Exhibits Exons Extracellular Matrix Eye Family Family member Functional disorder Gene Mutation Genes Genetic Genotype Goals Haplotypes Helix (Snails)Individual Ion Transport Keratoplasty Link Linkage Disequilibrium Lod Score Maps Microscopic Morphologic artifacts Mutation Numbers Operative Surgical Procedures Patients Penetrance Phenocopy Placement Population Population Group Predisposing Factor Proteins Quality Control Rate Research Personnel Risk Factors Screening procedure Sequence Analysis Staging Standards of Weights and Measures Stratification Technology Time United States Variant Visual Water base case control disability ear helix genetic linkage genetic linkage analysis genome wide association study genome-wide linkage genotyping technology improved insight kindred late disease onset member mutant novel proband programs receptor segregation size telomere

项目摘要

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.

描述：福克斯角膜营养不良 (FCD) 是一种退行性疾病，其特征是肠管增殖，肠管是支撑角膜内皮的富含胶原蛋白的细胞外基质的微小突起。 FCD 的初始阶段显示这些牙菌斑的数量逐渐增加，而末期疾病还表现出内皮功能缺陷，导致水流入和角膜基质严重混浊。肠管与这种内皮功能障碍有何关系仍不清楚。 40 岁或以上的人中约有 4% 受到 FCD 的影响。终末期疾病唯一有效的治疗方法是角膜移植手术，而 FCD 目前是此类手术最常见的原因。编码 VIII 型胶原蛋白亚基的 COL8A2 基因突变已明确与一种罕见的儿童期发病形式的 FCD 相关。 COL8A2 突变是否也与常见的成人发病形式有关尚不清楚。我们计划按如下方式研究成人发病的 FCD：1）我们最近将成人发病的 FCD 的第一个基因座定位到染色体 13pTel-q12.13 间隔，最大 LOD 得分为 3.91 和 3.80。我们计划完善该图谱并识别突变基因。 2) 我们对另外 3 个成人发病 FCD 的大家族进行全基因组连锁分析，结果显示，每个家族都与 18q21 的相同基因座连锁，外显率 85% 时，组合多点 LOD 评分为 5.94。当前疾病区间包含28个候选者；我们建议通过序列分析筛选候选基因并通过 SNP 单倍型关联更详细地绘制间隔来缩小间隔来识别基因。我们的长期目标是确定成人发病 FCD 的基因。最终，了解这些基因的身份将为了解疾病机制提供重要的见解。这将有助于改善福克斯角膜营养不良的早期诊断和开发非手术治疗方法。