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.
Highlights
Cataract is the leading cause of visual impairment worldwide, with approximately 37 million people affected, accounting for 48% of global blindness [1]
We report here that Eph receptor A2 gene (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
Summary
Cataract is the leading cause of visual impairment worldwide, with approximately 37 million people affected, accounting for 48% of global blindness [1]. Cataract is defined as any opacity of the crystalline lens resulting from either alteration in lens cell structure or changes in lens proteins or both. Morphologic classification of age-related cataract can be divided into four categories: nuclear, cortical, posterior subcapsular cataract and mixed type. Among Caucasian Americans aged 65 years or older, the reported prevalence of cortical cataract was 24% [2]. Incidence of cataract surgery in the United States is highest
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