Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pgen.1000584
Title: EPHA2 is associated with age-related cortical cataract in mice and humans
Authors: Jun G.
Guo H.
Klein B.E.K.
Klein R.
Jie J.W.
Mitchell P.
Miao H.
Lee K.E.
Joshi T.
Buck M.
Chugha P.
Bardenstein D.
Klein A.P.
Bailey-Wilson J.E.
Gong X.
Spector T.D.
Andrew T.
Hammond C.J.
Elston R.C.
Iyengar S.K.
Wang B. 
Keywords: arginine
ephrin receptor A2
glutamine
heat shock protein 25
heat shock protein 27
protein kinase
ephrin receptor A2
adult
age distribution
aged
aging
amino acid substitution
animal model
article
cataract
Caucasian
cell differentiation
cell stress
cell vacuole
chemical analysis
chromosome 1p
controlled study
disease course
disease duration
epithelium cell
exon
female
gene deletion
gene frequency
gene overexpression
genetic association
genetic linkage
genetic variability
human
illumination
lens
lens fiber
major clinical study
male
missense mutation
mouse
nonhuman
population based case control study
protein expression
protein folding
protein function
protein phosphorylation
receptor upregulation
retina macula age related degeneration
retroillumination
single nucleotide polymorphism
visual cortex
age
animal
C57BL mouse
cataract
chemistry
chromosome 1
cohort analysis
disease model
genetics
meta analysis
metabolism
middle aged
molecular genetics
mouse mutant
mutation
pathology
protein tertiary structure
sequence alignment
Murinae
Mus
Age Factors
Aged
Animals
Cataract
Chromosomes, Human, Pair 1
Cohort Studies
Disease Models, Animal
European Continental Ancestry Group
Female
Humans
Lens, Crystalline
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Molecular Sequence Data
Mutation
Polymorphism, Single Nucleotide
Protein Structure, Tertiary
Receptor, EphA2
Sequence Alignment
Visual Cortex
Issue Date: 2009
Citation: Jun G., Guo H., Klein B.E.K., Klein R., Jie J.W., Mitchell P., Miao H., Lee K.E., Joshi T., Buck M., Chugha P., Bardenstein D., Klein A.P., Bailey-Wilson J.E., Gong X., Spector T.D., Andrew T., Hammond C.J., Elston R.C., Iyengar S.K., Wang B. (2009). EPHA2 is associated with age-related cortical cataract in mice and humans. PLoS Genetics 5 (7) : e1000584. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pgen.1000584
Rights: Attribution 4.0 International
Abstract: Age-related cataract is a major cause of blindness worldwide, and cortical cataract is the second most prevalent type of agerelated 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. ©2009 Jun et al.
Source Title: PLoS Genetics
URI: https://scholarbank.nus.edu.sg/handle/10635/161673
ISSN: 15537390
DOI: 10.1371/journal.pgen.1000584
Rights: Attribution 4.0 International
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