Study of Genetic Basis of Fuchs Corneal Dystrophy

福克斯角膜营养不良的遗传基础研究

• 批准号: 7321157
• 负责人: GORDON KENNETH KLINTWORTH
• 金额: $ 50.02万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7321157
• 关键词: Affect; Bilateral; Candidate Disease Gene; Cells; Child; Chromosomes; Collection; Complex; Cornea; Corneal Endothelium; Corneal dystrophy; Data Set; Descemet' s membrane; Diagnostic tests; Disease; Early Diagnosis; Employee Strikes; Endothelial Cells; Etiology; Exhibits; Family; Family Study; Family member; Female; Frequencies; Functional disorder; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Research; Genome; Genotype; Goals; Inborn Genetic Diseases; Individual; Knowledge; Late-Onset Disorder; Lead; Maps; Methods; Molecular Diagnostic Testing; Mutation; Operative Surgical Procedures; Parents; Participant; Pathogenesis; Recruitment Activity; Research; Research Personnel; Rest; Risk; Sampling; Screening procedure; Siblings; Testing; Therapeutic procedure; Universities; Validation; age related; base; experience; follow-up; genetic linkage analysis; genetic risk factor; genome-wide linkage; interest; late disease onset; male; multidisciplinary; novel; novel therapeutics; positional cloning; proband; programs; sample collection; size

DESCRIPTION (provided by applicant): Fuchs corneal dystrophy (FCD) is a common bilateral late onset disorder of the corneal endothelium chracterized by a slowly progressive dysfunction of corneal endothelial cells associated with the loss of these cells and the formation of excrescences (corneal guttae) and excessive thickening of Descemet's membrane. This age-related disorder has a striking female:male preponderance. Evidence for Mendelian forms of FCD comes from large multigenerational FCD families. However, the majority of FCD are found in small families, which exhibit a complex form of FCD. FCD has also been mapped to loci on several chromosomes. The objective of this application by an experienced multidisciplinary team of investigators is to expand family recruitment and further our understanding of FCD with genetic studies. This study has five specific aims: (1) To continue recruiting families of FCD with at least one affected individual and up to two unaffected siblings as well as multigenerational FCD families, (2) To sequence and genotype the COL8A2 gene in each affected individual, (3) To perform a whole genome linkage screen using Illumina's fourth-generation SNP-based linkage panel, (4) To perform association mapping for up to four linkage regions to identify candidate genes associated with FCD and to follow up of these candidate genes, and (5) To perform positional cloning for large multigenerational families. To achieve these goals, an ocular examination will be performed on all participants to determine whether they are affected or not. Families with COL8A2 mutations will be removed from the linkage and follow-up analyses. Linkage analysis will be performed on various datasets of families of different size. This strategy will allow chromosonal regions that are responsible for Mendelian and complex forms of genetics in FCD to be identified. The long-term objective of this study is to understand the basic pathobiology of FCD and to identify genetic components of the disorder that will be valuable from the standpoint of developing molecular diagnostic tests for early diagnosis and for developing novel therapeutic procedures for this debilitating disease. Statement of Relevance: Knowledge about the genes that place individuals at risk for FCD will lead to a better understanding of this important disease, early diagnostic tests and novel non surgical methods of treatment.

描述（由申请人提供）：Fuchs角膜营养不良（FCD）是角膜内皮的常见双侧晚期发作障碍，该疾病通过与这些细胞的丧失以及descementecencences的损失以及descemets ancbrane ancbrane ancbrane ancbrane ancbrane ancbrane ancbrane and Corneal Endoperial细胞的缓慢进行性功能障碍。这种与年龄有关的疾病具有惊人的女性：男性优势。 Mendelian形式的FCD的证据来自大型多代FCD家庭。但是，大多数FCD都在小家族中发现，这些家庭表现出复杂的FCD形式。 FCD也已在几个染色体上映射到基因座。经验丰富的多学科研究人员的应用程序的目的是扩大家庭招聘，并通过遗传研究进一步了解FCD。这项研究具有五个具体目的：（1）继续招募至少有一个受影响的个体的FCD家族，最多有两个未受影响的兄弟姐妹以及多代FCD家族，（2）以序列和基因型COL8A2基因在每个受影响的个体中（3），（3）使用Illumina的四个基因链接（3），以执行Illumina的四个基本链接（3），以执行整个类型的链接（4）。连锁区域以识别与FCD相关的候选基因并跟进这些候选基因，以及（5）对大型多代家族进行位置克隆。为了实现这些目标，将对所有参与者进行眼检查，以确定它们是否受到影响。具有COL8A2突变的家庭将从连锁和后续分析中删除。链接分析将在不同大小的家族的各个数据集上进行。该策略将允许识别负责Mendelian和复杂遗传形式的染色体区域。这项研究的长期目的是了解FCD的基本病理生物学，并确定该疾病的遗传成分，从开发早期诊断的分子诊断测试的角度来看，这将是有价值的，并为这种衰弱的疾病开发了新的治疗方法。相关性：有关使个人面临FCD风险的基因的知识将使人们更好地了解这种重要的疾病，早期诊断测试和新型的非手术治疗方法。