Predisposed genetic variance and life-long metabolic and environmental stresses can impair lens homeostasis and contribute to age-related cataracts. Inadequate knowledge about genetic and environmental etiology of cataractogenesis hinders the development of non-surgical approaches to effectively delay or prevent age-related cataracts. Decades of studies have led to the identification of many gene mutations that cause hereditary cataracts. However, there has not been much progress in finding genetic modifiers that influence the severity and/or occurrence of cataracts. Identification of any cataractous genetic modifiers will be important for understanding the pathological progression of cataract formation and for developing an alternative non-surgical treatment that is currently unavailable to prevent or delay age-related cataracts. This project aims to identify the genetic modifiers that suppress nuclear cataract formation by using mouse genetic models. Lens connexin gene mutations cause cataracts in humans and in mice. Previous studies have demonstrated that the genetic background of different inbred strains influences the severity of nuclear cataracts caused by connexin mutations. Using a novel strategy, a combination of a genome-wide linage analysis of quantitative trait loci (QTLs), chromosome substitution by homologous counterparts from inbred strains and identification of SNPs from candidate genes, we have genetically dissected the complex traits for nuclear cataracts in connexin knockout mice. We have identified a semi-dominant suppressor of nuclear cataracts that located in a 2 million base pair interval on chromosome 7. The presence of this genetic modifier prevents dense nuclear cataracts in connexin mutant mice. After searching the polymorphic differences in the coding region and measuring the lens expression of a list of genes in this interval, we have selected 5 candidate genes. The primary goal of this project is to determine which candidate gene functions as a semi-dominant suppressor and to investigate the molecular basis for the prevention of nuclear cataracts. Moreover, we will continue to identify additional new genetic modifiers that suppress cataractogenesis. The information will be important for developing a new strategy to effectively prevent or delay nuclear cataracts, which account for about one-third of age-related cataracts.

Public Health Relevance

The primary goal of this project is to identify and characterize new genetic factors that suppress the formation of cataract. The new information from this study will be important not only for understanding the mechanism that controls the severity and/or onset of nuclear cataracts but also for developing a new non-surgical strategy to prevent and/or delay cataract formation.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Araj, Houmam H
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University of California Berkeley
Schools of Optometry/Ophthalmol
United States
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Cheng, Catherine; Ansari, Moham M; Cooper, Jonathan A et al. (2013) EphA2 and Src regulate equatorial cell morphogenesis during lens development. Development 140:4237-45
Cheng, Catherine; Gong, Xiaohua (2011) Diverse roles of Eph/ephrin signaling in the mouse lens. PLoS One 6:e28147
Xia, Chun-Hong; Lu, Eric; Liu, Haiquan et al. (2011) The role of Vldlr in intraretinal angiogenesis in mice. Invest Ophthalmol Vis Sci 52:6572-9
Mathias, Richard T; White, Thomas W; Gong, Xiaohua (2010) Lens gap junctions in growth, differentiation, and homeostasis. Physiol Rev 90:179-206
Alur, Ramakrishna P; Vijayasarathy, Camasamudram; Brown, Jacob D et al. (2010) Papillorenal syndrome-causing missense mutations in PAX2/Pax2 result in hypomorphic alleles in mouse and human. PLoS Genet 6:e1000870
Li, Lin; Cheng, Catherine; Xia, Chun-hong et al. (2010) Connexin mediated cataract prevention in mice. PLoS One 5:
Cheng, Catherine; Xia, Chun-hong; Huang, Qingling et al. (2010) Altered chaperone-like activity of alpha-crystallins promotes cataractogenesis. J Biol Chem 285:41187-93
Liu, Haiquan; Wang, Meng; Xia, Chun-Hong et al. (2010) Severe retinal degeneration caused by a novel rhodopsin mutation. Invest Ophthalmol Vis Sci 51:1059-65
Huang, Qingling; Ding, Linlin; Phan, Kim B et al. (2009) Mechanism of cataract formation in alphaA-crystallin Y118D mutation. Invest Ophthalmol Vis Sci 50:2919-26
DeRosa, Adam M; Mese, Gulistan; Li, Leping et al. (2009) The cataract causing Cx50-S50P mutant inhibits Cx43 and intercellular communication in the lens epithelium. Exp Cell Res 315:1063-75

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