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.
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.
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