Hereditary and developmental disorders are the cause of 20 percent of all blindness from chorioretinal diseases.
The specific aims of the current proposal are to characterize the molecular basis of mutations responsible for two inherited X- linked eye diseases - Ocular Albinism (OA1) and Retinitis Pigmentosa (RP2) which are localized on the short arm of X- chromosome. A novel subtraction cDNA cloning strategy will be used to isolate and identify the responsible loci in order to understand the pathogenesis of these hereditary disorders and to develop better probes for prenatal diagnosis and carrier detection. Mapping of eye/retina-specific cDNA clones during the project would be helpful in refining the physical and genetic linkage mao of the human X-chromosome and in identifying the candidate genes for other inherited X-linked eye diseases. The cDNA libraries from eye/retinal tissues and cells at various developmental stages will be prepared using a modified Charon lambda phage vector. Housekeeping genes for essential metabolic functions will be removed by hybridizing single stranded circular DNA from eye/retina cDNA libraries with biotinylated complementary RNA from human B-lymphocytes, and by subsequently separating the specific cDNAs by streptavidin-agarose chromatography. The subtracted cDNA clones enriched for eye/retina-specific messages will be selected for sequences encoded by the short arm of X-chromosome. The candidate genes will be identified by their map position. Analysis of linkage with the disease in affected families and of structural organization of genomic DNA from patients using candidate cDNA clones should lead to the identification of responsible genes for X-linked Ocular Albinism and Retinitis Pigmentosa. The long term objective of the PI is to investigate the molecular basis of the development of the visual system and associated genetic defects in human. Molecular analysis of genes for OA1 and RP2 will be the first step towards elucidating the nature of two diverse events during the development of visual function. The characterization of other X-linked eye and retina-specific clones, isolated during the project, will form the basis for future studies.

National Institute of Health (NIH)
National Eye Institute (NEI)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Visual Sciences A Study Section (VISA)
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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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
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
Hurd, Toby; Zhou, Weibin; Jenkins, Paul et al. (2010) The retinitis pigmentosa protein RP2 interacts with polycystin 2 and regulates cilia-mediated vertebrate development. Hum Mol Genet 19:4330-44
Patil, Suresh B; Verma, Rakesh; Venkatareddy, Madhusudan et al. (2010) Expression and localization of the ciliary disease protein retinitis pigmentosa GTPase regulator in mammalian kidney. Kidney Int 78:622-3
Paul, Erin; Kielbasinski, Marissa; Sedivy, John M et al. (2010) Widespread expression of the Supv3L1 mitochondrial RNA helicase in the mouse. Transgenic Res 19:691-701
O'Toole, John F; Liu, Yangjian; Davis, Erica E et al. (2010) Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy. J Clin Invest 120:791-802
Wu, D M; Khanna, H; Atmaca-Sonmez, P et al. (2010) Long-term follow-up of a family with dominant X-linked retinitis pigmentosa. Eye (Lond) 24:764-74

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