X-LINKED RETINITIS PIGMENTOSA

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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.