A defect in retinitis pigmentosa (RP) GTPase regulator (RPGR) causes X-linked RP, one of the most common and severe forms of inherited retinal degeneration. Progress towards understanding the RPGR function and disease mechanism is stymied by a lack of knowledge as to what constitutes the primary structure of a functional RPGR, due to the exceptional heterogeneity of RPGR transcript splicing which we document in Preliminary Studies in the current proposal. Our central hypothesis is that the N-terminal half of RPGR sequence encompassing the RCC1 homology domain constitutes the core functional module of RPGR. Functional constraint on the remainder of the primary sequence, with the exception of a highly conserved C-terminal tail, may be relaxed. This proposal will critically evaluate this hypothesis and will attempt to define the minimal RPGR primary structure sufficient for function, as defined by the ability to rescue the RPGR null phenotype. These studies are potentially of high impact as they will serve as the basis on which further studies may be carried out to determine RPGR function at the molecular level and to elucidate the pathogenic mechanism of RPGR mutations.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Small Research Grants (R03)
Project #
1R03EY014188-01A1
Application #
6610109
Study Section
Special Emphasis Panel (ZEY1-VSN (01))
Program Officer
Mariani, Andrew P
Project Start
2003-04-01
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
1
Fiscal Year
2003
Total Cost
$168,000
Indirect Cost
Name
Harvard University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Wright, Rachel N; Hong, Dong-Hyun; Perkins, Brian (2012) RpgrORF15 connects to the usher protein network through direct interactions with multiple whirlin isoforms. Invest Ophthalmol Vis Sci 53:1519-29
Wright, Rachel N; Hong, Dong-Hyun; Perkins, Brian (2011) Misexpression of the constitutive Rpgr(ex1-19) variant leads to severe photoreceptor degeneration. Invest Ophthalmol Vis Sci 52:5189-201
Hong, Dong-Hyun; Pawlyk, Basil S; Adamian, Michael et al. (2005) A single, abbreviated RPGR-ORF15 variant reconstitutes RPGR function in vivo. Invest Ophthalmol Vis Sci 46:435-41
Pawlyk, Basil S; Smith, Alexander J; Buch, Prateek K et al. (2005) Gene replacement therapy rescues photoreceptor degeneration in a murine model of Leber congenital amaurosis lacking RPGRIP. Invest Ophthalmol Vis Sci 46:3039-45