CANDIDATE GENES IN HEREDITARY CONGENITAL CATARACTS

这项修订建议基本上是研究的延续， 1990年开始进行分子鉴定和表征， 遗传性眼病相关基因的研究， 先天性白内障（CC）。CC，临床定义为 出生时存在透镜，约占人类视力丧失的10%。 据估计，三分之一的CC起源于遗传， 异质性常染色体显性先天性白内障（ADCC）形式， 最普遍的。提出的ADCC研究工作是基于 假设这种遗传异质性和表型 一组可变的疾病是由表达在细胞中的基因突变引起的。 胎儿的透镜。所提出的方法最好描述为 利用组织或功能特异性基因的候选基因方法 以及它们在图谱上的位置来识别致病基因。为此目的 候选基因的方法采用基因作图， 遗传变异，受影响家庭的连锁分析和 随后对候选基因内突变的表征显示， 与ADCC基因座共分离。ADCC的遗传异质性使其 有必要在大量的白内障患者中评估许多白内障候选基因， 家庭由于只有有限数量的白内障候选基因被发现， 目前，拟议工作的一个主要目标是隔离 新的基因优先在胎儿透镜中表达， 牛和人胎儿透镜cDNA文库的建立。我们假设 在胎儿透镜发育过程中活跃的基因导致了许多 ADCC是一种在出生时就出现的临床疾病。 同时，白内障候选基因探针库和ADCC 实验室的家庭数据库正在显著扩大 通过建立许多国家和国际 合作。另外45个ADCC家庭已被 确定。致病突变的最终鉴定 将增强对候选人正常功能的了解 基因及其在ADCC发病机制中的作用。这些知识与 与遗传连锁信息，将提高遗传的准确性 咨询，并可能允许更有效地治疗这种昂贵的 视觉障碍

This revised proposal is essentially a continuation of the studies initiated in 1990 on the molecular identification and characterization of genes related to hereditary eye diseases with a shift of focus toward congenital cataracts (CC). CC, clinically defined as opacities of the lens present at birth, account for roughly 10% of visual loss in humans. One-third of CC are estimated to be genetic in origin, with the heterogeneous autosomal dominant congenital cataract (ADCC) forms being the most prevalent. The proposed work on the study of ADCC is based on the assumption that this genetically heterogeneous and phenotypically variable group of disorders results from mutations in genes expressed in the fetal lens. The proposed approach can best be described as the candidate gene approach which utilizes tissue- or function-specific genes and their map position to identify disease-causing genes. To this end the candidate gene approach employs gene mapping, the identification of genetic variation, analysis of linkage in affected families and the subsequent characterization of mutations within candidate genes shown to cosegregate with ADCC loci. The genetic heterogeneity of ADCC makes it necessary to evaluate many cataract candidate genes in a large number of families. As only a limited number of cataract candidate genes are currently available, a major goal of the proposed work is the isolation of novel genes preferentially expressed in the fetal lens through the creation of bovine and human fetal lens cDNA libraries. We hypothesize that genes active during fetal lens development are responsible for many forms of ADCC, a disease which presents clinically at birth. Simultaneously, the pool of cataract candidate gene probes and the ADCC family database in the laboratory are being significantly expanded through the establishment of numerous national and international collaborations. Forty-five additional ADCC families have been ascertained. The ultimate identification of disease-causing mutations will enhance the understanding of the normal function of the candidate gene and its role in the pathogenesis of ADCC. This knowledge coupled with genetic linkage information, will improve the accuracy of genetic counseling and potentially permit more effective treatment of this costly visual disorder.