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 占盲人总数的0.01-0.04%。在大多数情况下，PCG 是一种常染色体隐性遗传和遗传易感性 被认为是这种情况发展的一个主要因素。 因此，我们建议识别和表征基因 通过遗传连锁分析和 位置映射。通过对多个受影响的家庭的研究 PCG，通过位置映射，我们的特定目标是绘制 PCG基因。为了实现这一点，我们已经确定和确定了 80多个家庭为盈科隔离。该小组由以下几个部分组成 105名患者(67名男性和38名女性)和173名先证者的同胞(84名男性和89名女性) 总共提供了261个潜在的信息性减数分裂。其中，总共 已经对25个家庭进行了抽样。我们挑选了一个19人的小组 作为我们最初的筛查小组，由2-4名受影响的同胞组成 和多达11个正常的兄弟姐妹。大多数受影响的孩子都是两个孩子 血缘婚姻，从而保证了隐性的继承模式。 这一小组由44个受影响的同胞和55个正常的同胞组成，总共提供 在99个潜在的信息减数中。通过使用此面板，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2q33-QTER，3q26-q27，远端部分 在6P、9P24-PTER、11P15、11Q12和16P中)，建议 与这种表型相关的。我们用聚合酶链式反应和银染技术 对我们的家系进行连锁评估(LOD评分法)。我们有 到目前为止，在17个DNA标记上进行了1317个基因分型，排除了PCG 来自染色体1，6和9的特定区域。我们将继续我们的 使用高度多态的DNA标记(即， 简单串联重复序列多态)。这一过程将继续下去，直到 PCG连锁的建立和遗传异质性的可能性 在盈科家族中进行了探索。饱和度映射与构造 然后，将启动PCG轨迹两侧的多点连锁图谱。如果 一种功能基因被确定为PCG筛查的原因 突变通过聚合酶链式反应-单链构象多态性来构建。这样做的长期目标是 建议是识别一种生物标记，可以用于 对高危人群进行产前检测和早期诊断。这将是 PCG基因克隆和鉴定的第一个关键步骤 个体突变可以解释确切的病理 导致这种情况的机制。这也将提供一个初始的 了解人眼的复杂性、其胚胎学和 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.