Cataract formation is the most common cause of vision loss, accounting for 51% of cases of blindness worldwide. In the US, cataract operations cost the Medicare system approximately $5 billion annually. Epidemiologic studies show that the pathogenesis of human cataracts involves genetic, environmental, and other disease-associated risk factors. In particular, 50% of childhood cataract cases have a genetic basis. The lens crystallins protein family accounts for 90% of lens proteins and plays a key role in lens transparency. Research has identified point mutations in the genes encoding ?-, -, and ?-crystallins, which lead to hereditary human cataract formation either at birth or at an early age. Functional studies on hereditary cataract formation could provide important information about the etiology of age-related cataracts. ?-crystallin is an aggregate of two polypeptides, ?A- and ?-crystallin, that are expressed in lens epithelial and fiber cells. Human patients harboring single point mutations in ?A- and ?-crystallin genes develop hereditary cataracts. To understand disease etiology in hereditary cataracts, we have used embryonic stem cell-based technologies to generate knock-in mice expressing proteins containing either the ?A-R49C or ?B-R120G mutation in ?-crystallins. These two mutations are associated with human autosomal dominant hereditary cataracts. We are also studying a knockout mouse lacking both ?A- and ?-crystallin. These mouse models develop cataracts at an early postnatal age and are important tools for understanding the disease process.
Our first aim will test the hypothesis that ?A-crystallin mutation or deletion causes upregulation of histone and metabolic enzyme expression in the developing lens at an early postnatal age.
The second aim will test the hypothesis that mutant ?A- or ?-crystalline disrupts normal lens protein homeostasis, leading to abnormal protein loss through autophagy. To address these aims, we will use complementary biochemical, cell biological and genetic approaches which are quantitative, objective and not subject to observer bias. The results of our studies will provide new insights into the molecular basis of lens development and cataract formation and promote the development of strategies to delay or prevent cataracts.

Public Health Relevance

Cataract formation - a clouding of the normally clear lens - is the most common cause of blindness worldwide. Cataract surgery is one of the largest expenses in the annual Medicare healthcare costs in the U.S. Cataracts are better known for affecting older people, but non-syndromic congenital cataracts occur at an early age and cause a significant visual impairment. Genetic and environmental factors have been found to play an important part in age-related cataracts. Crystallins are highly abundant proteins of the eye lens, and mutations in crystallins genes have been shown to be the cause of many inherited cataracts. Hereditary cataracts show clinically and genetically heterogeneous lens pathology, and the relationships between cataract etiology, morphology and underlying biochemical and cell biological mechanisms remain unclear. This project will address unanswered questions to understand the molecular mechanism for cataracts caused by two different mutations in alpha crystallin genes that cause human cataracts. Mechanistic studies of genetic mutations that cause early childhood cataracts are an important area of research particularly because of its implications to understand disease etiology for the more common age-related cataracts.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology of the Visual System Study Section (BVS)
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Araj, Houmam H
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Washington University
Schools of Medicine
Saint Louis
United States
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Hamilton, Paul D; Andley, Usha P (2018) In vitro interactions of histones and ?-crystallin. Biochem Biophys Rep 15:7-12
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Andley, Usha P; Goldman, Joshua W (2016) Autophagy and UPR in alpha-crystallin mutant knock-in mouse models of hereditary cataracts. Biochim Biophys Acta 1860:234-9
Makley, Leah N; McMenimen, Kathryn A; DeVree, Brian T et al. (2015) Pharmacological chaperone for ?-crystallin partially restores transparency in cataract models. Science 350:674-7
Andley, Usha P; Malone, James P; Townsend, R Reid (2014) In vivo substrates of the lens molecular chaperones ?A-crystallin and ?B-crystallin. PLoS One 9:e95507
Wignes, Jonathan A; Goldman, Joshua W; Weihl, Conrad C et al. (2013) p62 expression and autophagy in ?B-crystallin R120G mutant knock-in mouse model of hereditary cataract. Exp Eye Res 115:263-73
Andley, Usha P; Malone, James P; Hamilton, Paul D et al. (2013) Comparative proteomic analysis identifies age-dependent increases in the abundance of specific proteins after deletion of the small heat shock proteins ?A- and ?B-crystallin. Biochemistry 52:2933-48
Andley, Usha P; Hamilton, Paul D; Ravi, Nathan et al. (2011) A knock-in mouse model for the R120G mutation of *B-crystallin recapitulates human hereditary myopathy and cataracts. PLoS One 6:e17671
Andley, Usha P; Malone, James P; Townsend, R Reid (2011) Inhibition of lens photodamage by UV-absorbing contact lenses. Invest Ophthalmol Vis Sci 52:8330-41
Reilly, Matthew A; Andley, Usha P (2010) Quantitative biometric phenotype analysis in mouse lenses. Mol Vis 16:1041-6

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