EPHA2 Is Associated with Age-Related Cortical Cataract in Mice and Humans

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.Author Summary: Cataract is the leading cause of blindness. Cataract may form at any age, but the peak incidence is bimodal—in the perinatal period or later than 50 years of age. The early onset forms follow Mendelian inheritance patterns and are rare. Age-related cataract accounts for 18 million cases of blindness and 59 million cases of reduced vision worldwide. Among three types of age-related cataract, cortical cataract is known to be highly heritable, although few genes have been linked to its etiology. We report here that EPHA2 is associated with cortical cataract. EPHA2 is expressed in mouse and human cortical lens fiber cells, and homozygous deletion of Epha2 in two independent strains of mice led to development of cataract that progressed with age. Common and rare variants including a missense mutation in the EPHA2 gene were associated for cortical cataract in three different Caucasian populations. Our study identified EPHA2 as a gene for human age-related cataract and established Epha2 knockout mice as a model for progressive cortical cataract.