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EPHA2 is associated with age-related cortical cataract in mice and humans.

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.

SUBMITTER: Jun G

PROVIDER: S-EPMC2712078 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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EPHA2 is associated with age-related cortical cataract in mice and humans.

Jun Gyungah G Guo Hong H Klein Barbara E K BE Klein Ronald R Wang Jie Jin JJ Mitchell Paul P Miao Hui H Lee Kristine E KE Joshi Tripti T Buck Matthias M Chugha Preeti P Bardenstein David D Klein Alison P AP Bailey-Wilson Joan E JE Gong Xiaohua X Spector Tim D TD Andrew Toby T Hammond Christopher J CJ Elston Robert C RC Iyengar Sudha K SK Wang Bingcheng B

PLoS genetics 20090731 7

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 mon ...[more]

PMID: 19649315

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Project description:PURPOSE: The gene for Eph-receptor tyrosinekinase-type A2 (EPHA2) has been shown to be involved in the pathogenesis of age-related cataract (ARC). The aim of this study was to examine whether EPHA2 polymorphisms were associated with the susceptibility to age-related cortical cataract in a Han Chinese population. METHODS: Five single-nucleotide polymorphisms (SNPs)-rs3768293, rs3754334, rs7548209, rs707455, and rs477558-in the EPHA2 gene were genotyped in 422 Han Chinese patients with age-related cortical cataract and 317 age-, sex-, and ethnically matched healthy controls using a PCR restriction fragment length polymorphism (PCR-RFLP) assay. Data were analyzed by ?(2) analysis. RESULTS: The results showed that the five analyzed polymorphisms in EPHA2 were in Hardy-Weinberg equilibrium both in the patients and in the controls. The frequency of the rs477558 AA genotype was signi?cantly increased in ARC patients compared with controls (?(2)=8.649, pc=0.045, odds ratio [OR] 1.555, 95% CI 1.158 to 2.089). The frequency of the rs477558 AG genotype was signi?cantly decreased in ARC patients compared with controls (?(2)=9.281, pc=0.030, OR 0.626, 95% CI 0.463 to 0.847). Signi?cantly higher frequencies of the GG genotype and the G allele of rs7548209 were observed in ARC patients compared with controls (?(2)=10.430, pc=0.015, OR 1.660, 95% CI 1.219 to 2.261 and ?(2)=8.537, pc=0.015, OR 1.486, 95% CI 1.138 to 1.940, respectively). On the other hand, signi?cantly decreased frequencies of the rs7548209 CG genotype and the C allele were observed in ARC patients compared with controls (?(2)=9.999, pc=0.030, OR 0.603, 95% CI 0.440 to 0.826 and ?(2)=8.537, pc=0.015, OR 0.673, 95% CI 0.515 to 0.879, respectively). There was no difference in the frequencies of the genotype and allele of the rs3768293, rs3754334, and rs707455 SNPs between the patients with ARC and the controls. CONCLUSIONS: Our study suggests that both SNP rs477558 and SNP rs7548209 of EPHA2 are associated with age-related cortical cataract in a Han Chinese population.

Project description:ObjectiveWe investigated whether previously reported single nucleotide polymorphisms (SNPs) of EPHA2 in European studies are associated with cataract in India.MethodsWe carried out a population-based genetic association study. We enumerated randomly sampled villages in two areas of north and south India to identify people aged 40 and over. Participants attended a clinical examination including lens photography and provided a blood sample for genotyping. Lens images were graded by the Lens Opacification Classification System (LOCS III). Cataract was defined as a LOCS III grade of nuclear ≥4, cortical ≥3, posterior sub-capsular (PSC) ≥2, or dense opacities or aphakia/pseudophakia in either eye. We genotyped SNPs rs3754334, rs7543472 and rs11260867 on genomic DNA extracted from peripheral blood leukocytes using TaqMan assays in an ABI 7900 real-time PCR. We used logistic regression with robust standard errors to examine the association between cataract and the EPHA2 SNPs, adjusting for age, sex and location.Results7418 participants had data on at least one of the SNPs investigated. Genotype frequencies of controls were in Hardy-Weinberg Equilibrium (p>0.05). There was no association of rs3754334 with cataract or type of cataract. Minor allele homozygous genotypes of rs7543472 and rs11260867 compared to the major homozygote genotype were associated with cortical cataract, Odds ratio (OR) = 1.8, 95% Confidence Interval (CI) (1.1, 3.1) p = 0.03 and 2.9 (1.2, 7.1) p = 0.01 respectively, and with PSC cataract, OR = 1.5 (1.1, 2.2) p = 0.02 and 1.8 (0.9, 3.6) p = 0.07 respectively. There was no consistent association of SNPs with nuclear cataract or a combined variable of any type of cataract including operated cataract.ConclusionsOur results in the Indian population agree with previous studies of the association of EPHA2 variants with cortical cataracts. We report new findings for the association with PSC which is particularly prevalent in Indians.

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EPHA2 is associated with age-related cortical cataract in mice and humans.

Publications

EPHA2 is associated with age-related cortical cataract in mice and humans.

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