GENETIC LINKAGE STUDY OF PRIMARY CONGENITAL GLAUCOMA

原发性先天性青光眼（PCG）是一种遗传性眼病， 0.01-0.04%的盲人。 在大多数情况下，PCG 是作为常染色体隐性遗传性状和遗传再处置 被认为是这种情况发展的主要因素。 因此，我们建议识别和表征遗传 通过遗传连锁分析， 位置映射通过对多个受影响家庭的研究， PCG，通过位置映射，我们的具体目标是映射 PCG基因。为了实现这一目标，我们已经确定并确定了 超过80个家庭因PCG而被隔离该小组共包括 105例受影响者（67例男性和38例女性）和173例先证者同胞（84例男性和89例女性） 提供总共261个潜在的信息性减数分裂。其中， 已经对25个家庭进行了抽样调查。我们选出了一组19人 家庭作为我们的初步筛选小组，由2-4个受影响的同胞组成 以及多达11个正常同胞。大多数受影响的人都是两个人所生 近亲结婚，从而确保了隐性继承方式。 该小组由44个受影响的同胞和55个正常同胞组成，提供了总共 99个潜在的信息性减数分裂通过使用这个面板，我们计划 用一系列DNA标记寻找PCG的遗传连锁， 某些染色体的区域（即，2 q33-qter，3q 26-q27，远端部分 6p，9p24-pter，11p 15，11q12和16p）， 与这种表型有关。 我们使用PCR和银染色， 对家系进行连锁分析（LOD评分法）。我们有 到目前为止，对17个DNA标记进行了1,317个基因型分析， 来自染色体1、6和9的某些区域的基因座。我们将继续 使用高度多态性DNA标记从其它区域进行基因分型（即， 简单串联重复多态性）。这一进程将持续到 PCG的连锁建立和遗传异质性的可能性 PCG家族的研究。饱和度映射和构造 然后启动PCG基因座侧翼的多点连锁图谱。如果 一个功能基因被确定为PCG筛查的原因， 突变将通过PCR-SSCP构建。这一长期目标 建议是确定一种生物标志物，可用于 产前检查和早期诊断高危人群。这将是 PCG基因的克隆和鉴定的第一个关键步骤 个体突变可以解释 导致这种情况的机制。这也将提供一个初步的 了解人眼的复杂性，胚胎学和 功能，最终导致特定理性的发展 内科或外科治疗。

Primary Congenital Glaucoma (PCG) is an inherited eye disorder that is responsible for 0.01-0.04% of the blind people. In majority of cases PCG is inherited as an autosomal recessive trait and genetic redisposition regarded as a major factor in the development of this condition. Accordingly, we are proposing to identify and characterize the genetic factors underlying this condition by genetic linkage analysis and positional mapping. Through the study of multiply affected families with PCG, and by virtue of positional mapping our specific aim is to map the PCG gene. In order to achieve this, we have identified and ascertained over 80 families segregating for PCG. This panel is consist of a total of 105 affecteds (67 M & 38 F) and 173 sibs of probands (84 M & 89 F) providing a total of 261 potential informative meioses. Of these, a total of 25 families have already been sampled. We have selected a group of 19 families as our initial screening panel consisting of 2-4 affected sibs and up to 11 normal sibs. Most of the affected were born to two consanguineous marriages, thus ensuring the recessive mode of inheritance. This panel consists of 44 affected and 55 normal sibs, providing a total of 99 potential informative meioses. By using this panel, we are planning to search for genetic linkage of PCG with a series of DNA markers from region of certain chromosomes (i.e., 2q33-qter, 3q26-q27, distal portion of 6p, 9p24-pter, 11p 15, 11q12 and 16p) that are suggested to be associated with this phenotype. We use PCR and Silver staining to genotype our families for linkage evaluation (LOD score method). We have so far performed 1,317 genotypes on 17 DNA markers and excluded the PCG locus from certain regions of chromosomes 1, 6 and 9. We will continue our genotyping from other regions using highly polymorphic DNA markers (i.e., Simple Tandem Repeat Polymorphisms). This process will continue until the linkage of PCG is established and possibility of genetic heterogeneity amongst PCG families is explored. Saturation mapping and construction of multipoint linkage map flanking the PCG locus will then be initiated. If a functional gene is identified as the cause of PCG screening for mutations will be constituted by PCR-SSCP. The long term objective of this proposal is the identification of a biological marker that can be used for prenatal testing and early diagnosis of at risk individuals. This will be the first critical step for cloning of the PCG gene and identification of individual mutations which could explain the precise pathological mechanisms leading to this condition. This will also provide an initial step in understanding the complexity of the human eye, its embryology and function, that eventually leads to the development of specific rational medical or surgical treatment.