X-LINKED RETINITIS PIGMENTOSA

描述(改编自申请人摘要)：申请人建议 继续他们对X连锁逆转录病毒的研究。这个项目可以分成两部分 第一部分：RPGR基因突变的病理生理机制研究 以及(2)在没有遗传缺陷的患者中寻找基因缺陷 RPGR基因的突变。在项目的第一部分(目标1至3)， 申请人建议对RPGR基因及其基因产物进行表征 其目标是确定其生理功能并开发一种小鼠 通过创建RPGR零突变来建立X连锁RP模型。他们提议 对RPGR的频率和位置进行全面分析 他们的X连锁RP家族的突变，试图识别重要的 RPGR蛋白中的功能结构域以及建立基因 表型相关。申请者将调查亚细胞 RPGR蛋白的定位及鸟核苷酸交换分析 活性，并鉴定靶标GTPase和其他RPGR相互作用蛋白 视网膜和/或RPE。RPGR基因在小鼠体内将被破坏 同源重组研究疾病发病机制。在……里面 项目的第二部分(目标4和5)，申请者将尝试 鉴定X连锁RP患者的分子缺陷 RPGR突变。这将包括识别其他候选基因。 从RP3基因组区域以及提纯RP2和其他X连锁的 遗传上的RP基因座。

DESCRIPTION (Adapted from applicant's abstract): The applicants propose to continue their studies of X-linked RP. The project can be divided into two parts, (1) investigating the pathophysiologic mechanism of RPGR mutations and (2) searching for the genetic defect in patients that do not have mutations in the RPGR gene. In the first part of the project (aims 1 to 3), the applicants propose to characterize the RPGR gene and its gene product with the goal of defining its physiological function and to develop a mouse model of X-linked RP by creating an RPGR null mutation. They propose to perform a comprehensive analysis of the frequency and location of RPGR mutations in their X-linked RP families in an attempt to identify important functional domains in the RPGR protein as well as to establish genotype phenotype correlations. The applicants will investigate the subcellular location of the RPGR protein, assay its guanine nucleotide exchange activity, and identify target GTPase and other RPGR-interacting proteins in the retina and/or RPE. The RPGR gene will be disrupted in the mouse by homologous recombination to study the mechanism of disease pathogenesis. In the second part of the project (aims 4 and 5), the applicants will attempt to identify the molecular defects in X-linked RP patients who do not have RPGR mutations. This will include identifying additional candidate genes from the RP3 genomic region as well as refining the RP2 and other X-linked RP loci genetically.