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Genotype, Age, Genetic Background, and Sex Influence Epha2-Related Cataract Development in Mice

PURPOSE: Age-related cataract is the leading cause of blindness worldwide. Variants in the EPHA2 gene increase the disease risk, and its knockout in mice causes cataract. We investigated whether age, sex, and genetic background, risk factors for age-related cataract, and Epha2 genotype influence Eph...

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Autores principales: Dave, Alpana, Craig, Jamie E., Alamein, Mohammad, Skrzypiec, Karina, Beltz, Justin, Pfaff, Annalise, Burdon, Kathryn P., Ercal, Nuran, de Iongh, Robb U., Sharma, Shiwani
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Association for Research in Vision and Ophthalmology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431977/
https://www.ncbi.nlm.nih.gov/pubmed/34495288
http://dx.doi.org/10.1167/iovs.62.12.3
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author Dave, Alpana
Craig, Jamie E.
Alamein, Mohammad
Skrzypiec, Karina
Beltz, Justin
Pfaff, Annalise
Burdon, Kathryn P.
Ercal, Nuran
de Iongh, Robb U.
Sharma, Shiwani
author_facet Dave, Alpana
Craig, Jamie E.
Alamein, Mohammad
Skrzypiec, Karina
Beltz, Justin
Pfaff, Annalise
Burdon, Kathryn P.
Ercal, Nuran
de Iongh, Robb U.
Sharma, Shiwani
author_sort Dave, Alpana
collection PubMed
description PURPOSE: Age-related cataract is the leading cause of blindness worldwide. Variants in the EPHA2 gene increase the disease risk, and its knockout in mice causes cataract. We investigated whether age, sex, and genetic background, risk factors for age-related cataract, and Epha2 genotype influence Epha2-related cataract development in mice. METHODS: Cataract development was monitored in Epha2(+/+), Epha2(+/)(−), and Epha2(−)(/)(−) mice (Epha2(Gt(KST085)Byg)) on C57BL/6J and FVB:C57BL/6J (50:50) backgrounds. Cellular architecture of lenses, endoplasmic reticulum (ER) stress, and redox state were determined using histological, molecular, and analytical techniques. RESULTS: Epha2(−)(/)(−) and Epha2(+/)(−) mice on C57BL/6J background developed severe cortical cataracts by 18 and 38 weeks of age, respectively, compared to development of similar cataract significantly later in Epha2(−)(/)(−) mice and no cataract in Epha2(+/)(−) mice in this strain on FVB background, which was previously reported. On FVB:C57BL/6J background, Epha2(−)(/)(−) mice developed severe cortical cataract by 38 weeks and Epha2(+/)(−) mice exhibited mild cortical cataract up to 64 weeks of age. Progression of cataract in Epha2(−)(/)(−) and Epha2(+/)(−) female mice on C57BL/6J and mixed background, respectively, was slower than in matched male mice. N-cadherin and β-catenin immunolabeling showed disorganized lens fiber cells and disruption of lens architecture in Epha2(−)(/)(−) and Epha2(+/)(−) lenses, coinciding with development of severe cataracts. EPHA2 immunolabeling showed intracellular accumulation of the mutant EPHA2-β-galactosidase fusion protein that induced a cytoprotective ER stress response and in Epha2(+/)(−) lenses was also accompanied by glutathione redox imbalance. CONCLUSIONS: Both, Epha2(−)(/)(−) and Epha2(+/)(−) mice develop age-related cortical cataract; age as a function of Epha2 genotype, sex, and genetic background influence Epha2-related cataractogenesis in mice.
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spelling pubmed-84319772021-09-24 Genotype, Age, Genetic Background, and Sex Influence Epha2-Related Cataract Development in Mice Dave, Alpana Craig, Jamie E. Alamein, Mohammad Skrzypiec, Karina Beltz, Justin Pfaff, Annalise Burdon, Kathryn P. Ercal, Nuran de Iongh, Robb U. Sharma, Shiwani Invest Ophthalmol Vis Sci Lens PURPOSE: Age-related cataract is the leading cause of blindness worldwide. Variants in the EPHA2 gene increase the disease risk, and its knockout in mice causes cataract. We investigated whether age, sex, and genetic background, risk factors for age-related cataract, and Epha2 genotype influence Epha2-related cataract development in mice. METHODS: Cataract development was monitored in Epha2(+/+), Epha2(+/)(−), and Epha2(−)(/)(−) mice (Epha2(Gt(KST085)Byg)) on C57BL/6J and FVB:C57BL/6J (50:50) backgrounds. Cellular architecture of lenses, endoplasmic reticulum (ER) stress, and redox state were determined using histological, molecular, and analytical techniques. RESULTS: Epha2(−)(/)(−) and Epha2(+/)(−) mice on C57BL/6J background developed severe cortical cataracts by 18 and 38 weeks of age, respectively, compared to development of similar cataract significantly later in Epha2(−)(/)(−) mice and no cataract in Epha2(+/)(−) mice in this strain on FVB background, which was previously reported. On FVB:C57BL/6J background, Epha2(−)(/)(−) mice developed severe cortical cataract by 38 weeks and Epha2(+/)(−) mice exhibited mild cortical cataract up to 64 weeks of age. Progression of cataract in Epha2(−)(/)(−) and Epha2(+/)(−) female mice on C57BL/6J and mixed background, respectively, was slower than in matched male mice. N-cadherin and β-catenin immunolabeling showed disorganized lens fiber cells and disruption of lens architecture in Epha2(−)(/)(−) and Epha2(+/)(−) lenses, coinciding with development of severe cataracts. EPHA2 immunolabeling showed intracellular accumulation of the mutant EPHA2-β-galactosidase fusion protein that induced a cytoprotective ER stress response and in Epha2(+/)(−) lenses was also accompanied by glutathione redox imbalance. CONCLUSIONS: Both, Epha2(−)(/)(−) and Epha2(+/)(−) mice develop age-related cortical cataract; age as a function of Epha2 genotype, sex, and genetic background influence Epha2-related cataractogenesis in mice. The Association for Research in Vision and Ophthalmology 2021-09-08 /pmc/articles/PMC8431977/ /pubmed/34495288 http://dx.doi.org/10.1167/iovs.62.12.3 Text en Copyright 2021 The Authors https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License.
spellingShingle Lens
Dave, Alpana
Craig, Jamie E.
Alamein, Mohammad
Skrzypiec, Karina
Beltz, Justin
Pfaff, Annalise
Burdon, Kathryn P.
Ercal, Nuran
de Iongh, Robb U.
Sharma, Shiwani
Genotype, Age, Genetic Background, and Sex Influence Epha2-Related Cataract Development in Mice
title Genotype, Age, Genetic Background, and Sex Influence Epha2-Related Cataract Development in Mice
title_full Genotype, Age, Genetic Background, and Sex Influence Epha2-Related Cataract Development in Mice
title_fullStr Genotype, Age, Genetic Background, and Sex Influence Epha2-Related Cataract Development in Mice
title_full_unstemmed Genotype, Age, Genetic Background, and Sex Influence Epha2-Related Cataract Development in Mice
title_short Genotype, Age, Genetic Background, and Sex Influence Epha2-Related Cataract Development in Mice
title_sort genotype, age, genetic background, and sex influence epha2-related cataract development in mice
topic Lens
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431977/
https://www.ncbi.nlm.nih.gov/pubmed/34495288
http://dx.doi.org/10.1167/iovs.62.12.3
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