CANDIDATE GENES IN HEREDITARY CONGENITAL CATARACTS

这项经修订的建议基本上是研究的延续。 于1990年在分子鉴定和表征方面发起 与遗传性眼病相关的基因，重点转移到 先天性白内障(CC)。CC，临床上定义为眼球混浊 晶状体在出生时就存在，约占人类视力损失的10%。 据估计，三分之一的CC起源于遗传，其中 异质性常染色体显性遗传性先天性白内障 最普遍的。关于ADCC研究的拟议工作是基于 假设这种遗传异质性和表型 一组可变的疾病是由基因表达突变引起的 胎儿的晶状体。建议的方法可以最好地描述为 利用组织或功能特异基因的候选基因方法 以及它们识别致病基因的图谱位置。为此， 候选基因方法采用基因作图的方法，鉴定 受影响家系的遗传变异、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候选基因中进行评估 家人。因为只有有限数量的白内障候选基因是 目前，拟议工作的一个主要目标是隔离 在胎儿晶状体中优先表达的新基因 牛和人胎儿晶状体cDNA库的构建。我们假设 在胎儿晶状体发育过程中活跃的基因对许多 ADCC的各种形式，这是一种出生时就出现的临床症状。 同时，白内障候选基因探针库和ADCC 实验室中的家庭数据库正在显著扩展 通过建立无数的国家和国际组织 合作。另外45个ADCC家庭已经被 已经确定了。致病突变的最终鉴定 将加强对应聘者正常职能的理解 基因及其在ADCC发病机制中的作用。这种知识结合在一起 有了遗传连锁信息，将提高遗传的准确性 咨询和潜在地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.