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.
Jun
Gyungah
G
Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
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
D000367:Age Factors; D000368:Aged; D000818:Animals; D002386:Cataract / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D015331:Cohort Studies; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007908:Lens, Crystalline / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D036104:Receptor, EphA2 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016415:Sequence Alignment; D014793:Visual Cortex / Q000737:chemistry / Q000378:metabolism; D044465:White People / Q000235:genetics
D036104:Receptor, EphA2