A GENETIC APPROACH TO THE ROLE OF CYP1B1 IN PCG

CYP1B1 在 PCG 中作用的遗传学方法

• 批准号: 6658957
• 负责人: Bassem A Bejjani
• 金额: $ 33.03万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6658957
• 关键词: Arab country; Arabs; Ecuador; South American; alleles; clinical research; congenital eye disorder; cytochrome P450; developmental genetics; enzyme substrate; family genetics; gene expression; gene frequency; gene mutation; genetic markers; genotype; glaucoma; human genetic material tag; human population study; human subject; in situ hybridization; laboratory mouse; linkage mapping; molecular cloning; nucleic acid sequence; polymerase chain reaction

DESCRIPTION (Adapted from applicant's abstract): Primary Congenital Glaucoma (PCG) is an autosomal recessive disorder caused by developmental defect(s) of the anterior chamber angle. We and others have shown that homozygous or compound heterozygous mutations in CYP1B1, the gene for cytochrome P4501B1, are the principal cause for PCG. We documented variable expressivity and decreased penetrance for the PCG phenotype in the Saudi population and showed evidence for genetic heterogeneity in the Saudi and Ecuadorian populations. However, our observations also suggest that a major modifier locus causing decreased penetrance is present in the Saudi population and that this locus is dominant and unique to this population. This proposal aims to map and to clone the modifier of CYP1B1 action in the Saudi population, and to map and clone other PCG-causing genes. This application also seeks to define the developmental expression of CYP1B1 in mouse development as a first step towards understanding the role of this enzyme in normal and glaucomatous eye development. Finally, biochemical studies on sera from PCG patients will address the identity of the physiologic substrate of CYP1B1. For these ends, we will map the putative modifier of the PCG phenotype by parametric and nonparametric methods in an unique cohort of Saudi Arabian families. Our initial studies have already shown that the families in hand provide enough information to map such a modifier. Positional candidate genes will be excluded by combined positional/functional approaches. Families from Saudi Arabia and Ecuador will be used also to map additional PCG loci. Study of the developmental expression of CYP1B1 by RNA in situ hybridization in mouse will establish an expression profile for this gene in various ocular and extra-ocular tissues. The discovery of a modifier for the glaucoma phenotype and the identification of the physiologic substrate for CYP1B1 have the potential of improving our understanding of the normal development of the anterior chamber and of the structure and function of the aqueous humor outflow pathways at the cellular and molecular level. They could also provide new avenues for treatment of PCG and possibly other forms of glaucoma.

描述（改编自申请人的摘要）：原发性先天青光眼 （PCG）是由发育缺陷引起的常染色体隐性疾病 前室角。我们和其他人已经表明了纯合或 CYP1B1中的复合杂合突变，细胞色素P4501B1的基因 PCG的主要原因。我们记录了变量表达性并降低 沙特人口中PCG表型的外观，并显示了证据 用于沙特和厄瓜多尔人口中的遗传异质性。但是，我们的 观察结果还表明，导致降低的主要修饰符基因座 沙特人口中存在渗透率，并且该基因座是主导的 这是这个人群独有的。该建议旨在映射并克隆 沙特人口中CYP1B1动作的修饰符，并绘制和克隆其他 引起PCG的基因。该应用程序还旨在定义发展 CYP1B1在鼠标开发中的表达是理解的第一步 该酶在正常和青光眼发育中的作用。最后， PCG患者血清的生化研究将解决 CYP1B1的生理基板。对于这些目的，我们将绘制假定的 通过参数和非参数方法的PCG表型的修饰符 沙特阿拉伯家庭的独特队列。我们的最初研究已经表明 手头的家庭提供了足够的信息来绘制这种修饰符。 位置候选基因将被联合位置/功能排除在外 方法。来自沙特阿拉伯和厄瓜多尔的家庭也将用于绘制 其他PCG基因座。研究RNA中CYP1B1的发育表达 小鼠中的原位杂交将建立该基因的表达曲线 在各种眼和眼外组织中。发现的修饰符 青光眼表型和生理底物的鉴定 CYP1B1有可能提高我们对正常的理解 前室的发展以及结构和功能 在细胞和分子水平上的水性幽默流出途径。他们可以 还提供了治疗PCG和可能其他形式的新途径 青光眼。