EPHA2 Is Associated with Age-Related Cortical Cataract in Mice and Humans
Year: 2009
Type: article
Abstract: Age-related cataract is a major cause of blindness worldwide, and cortical cataract is the second most prevalent type of age-related cataract. Although a significant fraction of age-related cataract is heritable, the genetic basis remains to be elucidated. We report that homozygous deletion of Epha2 in two independent strains of mice developed progressive cortical cataract. Retroillumination revealed development of cortical vacuoles at one month of age; visible cataract appeared around three months, which progressed to mature cataract by six months. EPHA2 protein expression in the lens is spatially and temporally regulated. It is low in anterior epithelial cells, upregulated as the cells enter differentiation at the equator, strongly expressed in the cortical fiber cells, but absent in the nuclei. Deletion of Epha2 caused a significant increase in the expression of HSP25 (murine homologue of human HSP27) before the onset of cataract. The overexpressed HSP25 was in an underphosphorylated form, indicating excessive cellular stress and protein misfolding. The orthologous human EPHA2 gene on chromosome 1p36 was tested in three independent worldwide Caucasian populations for allelic association with cortical cataract. Common variants in EPHA2 were found that showed significant association with cortical cataract, and rs6678616 was the most significant in meta-analyses. In addition, we sequenced exons of EPHA2 in linked families and identified a new missense mutation, Arg721Gln, in the protein kinase domain that significantly alters EPHA2 functions in cellular and biochemical assays. Thus, converging evidence from humans and mice suggests that EPHA2 is important in maintaining lens clarity with age.
Source: PLoS Genetics
Authors: Gyungah Jun, Hong Guo, Barbara E. K. Klein, Ronald Klein, Jie Jin Wang, Paul Mitchell, Hui Miao, Kristine E. Lee, Tripti Joshi, Matthias Buck, Preeti Chugha, David Bardenstein, Alison P. Klein, Joan E. Bailey-Wilson, Xiaohua Gong, Tim D. Spector, Toby Andrew, Christopher J. Hammond, Robert C. Elston, Sudha K. Iyengar, Bingcheng Wang
Institutions: Case Western Reserve University, Case Comprehensive Cancer Center, University of Wisconsin–Madison, The University of Sydney, The University of Melbourne, Westmead Hospital, Centre for Eye Research Australia, Johns Hopkins University, Johns Hopkins Medicine, Sidney Kimmel Comprehensive Cancer Center, National Institutes of Health, National Human Genome Research Institute, University of California, San Francisco, University of California, Berkeley, St Thomas' Hospital, King's College London
Language: English
Topic: Connexins and lens biology
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,043
Funders: Wellcome Trust, Versus Arthritis, National Institutes of Health, National Health and Medical Research Council, National Human Genome Research Institute, National Eye Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources
Awards: G1097323614, G1697481817, G1873684677, G2011085462, G2153585430, G2272467506, G2391991125, G2409831680, G2509621741, G2564296191, Blue Mountains Cohort Study, EphA2 Agonists as Novel Inhibitors of Tumor Progression, G2957628220, G3917990051, G3960757247, G4132518751, G4425141122, GENETIC ANALYSIS OF MULTIFACTORIAL TRAITS, G49068929, G528900922, G5359555627, G5872832005, G6194375762, G6993196566, Fine Mapping of Genes for Age-Related Maculopathy, G8366642434, G89674864
OpenAlex ID: W1998007541