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Genotype, age, genetic background, and sex influence Epha2-related cataract development in mice

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Dave, A, Craig, JE, Alamein, M, Skrzypiec, K, Beltz, J, Pfaff, A, Burdon, KP ORCID: 0000-0001-8217-1249, Ercal, N, de Iongh, RU and Sharma, S 2021 , 'Genotype, age, genetic background, and sex influence Epha2-related cataract development in mice' , Investigative Ophthalmology and Visual Science, vol. 62, no. 12 , pp. 1-16 , doi: 10.1167/iovs.62.12.3.

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Abstract

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 (Epha2Gt(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.

Item Type: Article
Authors/Creators:Dave, A and Craig, JE and Alamein, M and Skrzypiec, K and Beltz, J and Pfaff, A and Burdon, KP and Ercal, N and de Iongh, RU and Sharma, S
Keywords: Epha2, biological factors, mouse model, age-related cataract, risk factors, genetics
Journal or Publication Title: Investigative Ophthalmology and Visual Science
Publisher: Assoc Research Vision Ophthalmology Inc
ISSN: 0146-0404
DOI / ID Number: 10.1167/iovs.62.12.3
Copyright Information:

Copyright 2021 The Authors. This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) License, (https://creativecommons.org/licenses/by/4.0/)

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