Abstract

Our long-term objective is to successfully intervene in the progression of primary open-angle glaucoma (POAG), one of the leading causes of blindness in the world. Early detection of POAG and treatment has proven to be one of the most successful ways to stop blindness from ensuing. The causes of POAG are numerous involving both environmental and genetic determinants. Several forms of POAG have been shown to result from a specific gene defect. Our lab is pursuing the identification of the GLC1C and GLC1F POAG genes. A small isolated pocket of Northern Greece, Epirus, may hold an important key to identifying the POAG GLC1C gene. A large family from Epirus with over 12 individuals with POAG carries the GLC1C gene. We propose that GLC1C is the major POAG gene in this region based on the isolation of the population with little or no interaction with outside populations over the last two centuries. If so, haplotype analysis of Epirian families and individuals with POAG, will identify a founder chromosome and should dramatically reduce the size of the GLC1C region to be searched for the POAG gene. A similar strategy will be used to analyze US and Australian POAG families that show positive evidence for linkage to GLC1C or GLC1F. Identification of a GLC1C and a GLC1F founder haplotype could be used as a screening tool for detecting POAG individuals carrying either the GLC1C or GLC1F gene. While screening tools are important, identification of the GLC1C and GLC1F genes is our ultimate goal. Mutational analysis of candidate genes contained within the GLC1C and GLC1F regions refined by haplotype analysis will be a major goal of this proposal, The last aim of this proposal will be to analyze our Greek and US POAG families and random POAG individuals for mutations in the known POAG genes, MYOC and OPTN. Identification and characterization of the GLC1C and GLC1F POAG genes will point the way to new avenues for research for treatment and/or prevention of blindness resulting from POAG.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011650-11
Application #
7269890
Study Section
Special Emphasis Panel (ZRG1-VISA (01))
Program Officer
Chin, Hemin R
Project Start
1997-08-01
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2009-07-31
Support Year
11
Fiscal Year
2007
Total Cost
$507,112
Indirect Cost

  Institution

Name
Oregon Health and Science University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239

  Publications

Keller, Kate E; Wirtz, Mary K (2017) Working your SOCS off: The role of ASB10 and protein degradation pathways in glaucoma. Exp Eye Res 158:154-160
Keller, Kate E; Yang, Yong-Feng; Sun, Ying Ying et al. (2014) Interleukin-20 receptor expression in the trabecular meshwork and its implication in glaucoma. J Ocul Pharmacol Ther 30:267-76
Keller, Kate E; Yang, Yong-Feng; Sun, Ying Ying et al. (2013) Ankyrin repeat and suppressor of cytokine signaling box containing protein-10 is associated with ubiquitin-mediated degradation pathways in trabecular meshwork cells. Mol Vis 19:1639-55
Sengle, Gerhard; Tsutsui, Ko; Keene, Douglas R et al. (2012) Microenvironmental regulation by fibrillin-1. PLoS Genet 8:e1002425
Pasutto, Francesca; Keller, Kate E; Weisschuh, Nicole et al. (2012) Variants in ASB10 are associated with open-angle glaucoma. Hum Mol Genet 21:1336-49
Charlesworth, Jac; Kramer, Patricia L; Dyer, Tom et al. (2010) The path to open-angle glaucoma gene discovery: endophenotypic status of intraocular pressure, cup-to-disc ratio, and central corneal thickness. Invest Ophthalmol Vis Sci 51:3509-14
Wirtz, Mary K; Samples, John R; Toumanidou, Victoria et al. (2010) Association of POAG risk factors and the Thr377Met MYOC mutation in an isolated Greek population. Invest Ophthalmol Vis Sci 51:3055-60
Wirtz, Mary K; Konstas, Anastasios G P; Samples, John R et al. (2008) Myocilin variations and familial glaucoma in Taxiarchis, a small Greek village. Mol Vis 14:774-81
Hewitt, Alex W; Samples, John R; Allingham, R Rand et al. (2007) Investigation of founder effects for the Thr377Met Myocilin mutation in glaucoma families from differing ethnic backgrounds. Mol Vis 13:487-92
Wirtz, Mary K; Samples, John R; Choi, Dongseok et al. (2007) Clinical features associated with an Asp380His Myocilin mutation in a US family with primary open-angle glaucoma. Am J Ophthalmol 144:75-80

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