GENETIC LINKAGE STUDY MACULAR CORNEAL DYSTROPHY

黄斑角膜营养不良的遗传连锁研究

• 批准号: 3265483
• 负责人: GORDON KENNETH KLINTWORTH
• 金额: $ 14.76万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-01 至 1994-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3265483
• 关键词: DNA; autosomal recessive trait; biological polymorphism; enzyme linked immunosorbent assay; gene expression; genetic markers; genetic registry /resource /referral center; keratan sulfate; keratomalacia; linkage mapping; nucleic acid sequence; patient /disease registry; tissue /cell culture

Macular corneal dystrophy (MCD) is a rare, autosomal recessive ocular storage disease which leads to progressive bilateral visual loss. Clinical progression of the disease usually causes visual impairment during the second decade of life and generally worsens until penetrating keratoplasty (cornea transplantation) is required to restore vision usually by the fourth decade of life. A keratan sulfate like glycosaminoglycan accumulates in the cornea. The location of the gene for MCD is unknown and no presymptomatic diagnostic test is available to individuals who are at risk. Nor is there a reliable form of carrier detection. The objective of the proposed research is to define the genomic location of the MCD gene(s) while concurrently attempting to characterize the storage substance. Participants will be selected from a registry of affected individuals and their unaffected relatives maintained by the Principal Investigator. Blood samples will be obtained from affected individuals, their parents, and siblings to establish lymphoblastoid cell lines as permanent sources of DNA. In addition, serum will be tested for a specific epitope of sulfated keratan sulfate which is known to be markedly reduced in many affected individuals. Linkage analysis of MCD with restriction fragment length polymorphisms randomly located throughout the genome as well as candidate genes that become available will be performed using state-of-the-art statistical methodology. The establishment of a linkage relationship and identification of the chromosomal location are the first steps in identifying the gene. Fine gene mapping, gene expression, the nature of the abnormal accumulates, and its mechanism of generation may then be possible. In addition establishment of linkage relationships may clarify the possibility of genetic heterogeneity in this disorder. These developments will lead to a method of presymptomatic diagnosis of MCD and detection of carriers of the MCD gene. Eventually the work may lead to an alternative means of treating MCD when further techniques of genetic engineering become available.

黄斑角膜营养不良（MCD）是一种罕见的常染色体隐性眼 储存疾病会导致进行性双边视觉丧失。 临床 疾病的进展通常会导致视觉障碍 生命的第二个十年，通常会恶化，直到穿透角膜生成形术 （角膜移植）通常需要恢复视力 生命的第四个十年。 像糖胺聚糖这样的硫酸葡萄糖 积聚在角膜中。 MCD基因的位置未知，并且 在 风险。 也没有可靠的载体检测形式。 拟议研究的目的是定义 MCD基因同时尝试表征存储 物质。 参与者将从受影响的注册表中选出 个人及其不受影响的亲戚由校长维护 研究者。 血液样本将从受影响的个体中获得 他们的父母和兄弟姐妹以建立淋巴母细胞细胞系 永久性DNA来源。 此外，还将测试血清的特定 硫酸硫酸角质硫酸盐的表位，已知已明显降低 在许多受影响的人中。 限制MCD的链接分析 片段长度多态性随机地位于整个基因组中 以及可用的候选基因将使用 最先进的统计方法。 建立联系关系和确定 染色体位置是识别基因的第一步。 美好的 基因映射，基因表达，异常积累的性质， 然后，它的发电机理可能是可能的。 此外 建立联系关系可能会阐明 这种疾病中的遗传异质性。 这些发展将导致 MCD的预症状诊断和检测的方法 MCD基因。 最终，这项工作可能会导致一种治疗的替代方法 MCD当基因工程的进一步技术可用时。