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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY007961-13
Application #
6138148
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Dudley, Peter A
Project Start
1990-07-01
Project End
2001-12-31
Budget Start
2000-01-01
Budget End
2000-12-31
Support Year
13
Fiscal Year
2000
Total Cost
$338,998
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Beltran, William A; Cideciyan, Artur V; Lewin, Alfred S et al. (2014) Gene augmentation for X-linked retinitis pigmentosa caused by mutations in RPGR. Cold Spring Harb Perspect Med 5:a017392
Anand, Manisha; Khanna, Hemant (2012) Ciliary transition zone (TZ) proteins RPGR and CEP290: role in photoreceptor cilia and degenerative diseases. Expert Opin Ther Targets 16:541-51
Thompson, Debra A; Khan, Naheed W; Othman, Mohammad I et al. (2012) Rd9 is a naturally occurring mouse model of a common form of retinitis pigmentosa caused by mutations in RPGR-ORF15. PLoS One 7:e35865
Branham, Kari; Othman, Mohammad; Brumm, Matthew et al. (2012) Mutations in RPGR and RP2 account for 15% of males with simplex retinal degenerative disease. Invest Ophthalmol Vis Sci 53:8232-7
Beltran, William A; Cideciyan, Artur V; Lewin, Alfred S et al. (2012) Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa. Proc Natl Acad Sci U S A 109:2132-7
Chakarova, Christina F; Khanna, Hemant; Shah, Amna Z et al. (2011) TOPORS, implicated in retinal degeneration, is a cilia-centrosomal protein. Hum Mol Genet 20:975-87
Murga-Zamalloa, Carlos A; Ghosh, Amiya K; Patil, Suresh B et al. (2011) Accumulation of the Raf-1 kinase inhibitory protein (Rkip) is associated with Cep290-mediated photoreceptor degeneration in ciliopathies. J Biol Chem 286:28276-86
Yao, Jingyu; Feathers, Kecia L; Khanna, Hemant et al. (2011) XIAP therapy increases survival of transplanted rod precursors in a degenerating host retina. Invest Ophthalmol Vis Sci 52:1567-72
Otto, Edgar A; Hurd, Toby W; Airik, Rannar et al. (2010) Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy. Nat Genet 42:840-50
Murga-Zamalloa, Carlos A; Atkins, Stephen J; Peranen, Johan et al. (2010) Interaction of retinitis pigmentosa GTPase regulator (RPGR) with RAB8A GTPase: implications for cilia dysfunction and photoreceptor degeneration. Hum Mol Genet 19:3591-8

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