Cataract is a leading cause of vision loss and accounts for -45% of blindness worldwide. Epidemiological studies have shown that cataract is a multi-factorial disease involving genetic and environmental factors. The goal of this study is to improve understanding of the molecular genetic basis of cataract. The proposal has three specific aims.
In specific aim 1, we will use cell transfection and transgenic mouse techniques to characterize the pathogenic effects of a mutation in a novel gene for inherited cataract.
In specific aim 2, we will use expression-profiling and mutation-profiling techniques to identify a novel gene for inherited cataract.
In specific aim 3, we will use a custom re-sequencing array to test for association between genes for inherited cataract and age-related cataract. Results from these genetic studies will 1) provide new insights regarding the molecular basis of lens development and aging, 2) contribute to the design of gene-based diagnostics and therapeutics for cataract management, and 3) enable better evaluation of the gene-gene versus gene-environment interactions underlying cataract development. Public health relevance: Cataract afflicts more than 20 million Americans over age 40 and is the most common reason for eye surgery, accounting for -60% of the Medicare vision budget. Cataract is also a significant cause of visual impairment in childhood.
This research aims to identify and characterize genetic factors that cause cataract to run in families and develop new ways to diagnose, treat and even prevent cataract.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Chin, Hemin R
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Washington University
Schools of Medicine
Saint Louis
United States
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Bennett, Thomas M; M'Hamdi, Oussama; Hejtmancik, J Fielding et al. (2017) Germ-line and somatic EPHA2 coding variants in lens aging and cataract. PLoS One 12:e0189881
Bennett, Thomas M; Zhou, Yuefang; Shiels, Alan (2016) Lens transcriptome profile during cataract development in Mip-null mice. Biochem Biophys Res Commun 478:988-93
Zhou, Yuefang; Bennett, Thomas M; Shiels, Alan (2016) Lens ER-stress response during cataract development in Mip-mutant mice. Biochim Biophys Acta 1862:1433-42
Shiels, Alan; Hejtmancik, J Fielding (2015) Molecular Genetics of Cataract. Prog Mol Biol Transl Sci 134:203-18
Hejtmancik, J Fielding; Shiels, Alan (2015) Overview of the Lens. Prog Mol Biol Transl Sci 134:119-27
Mackay, Donna S; Bennett, Thomas M; Shiels, Alan (2015) Exome Sequencing Identifies a Missense Variant in EFEMP1 Co-Segregating in a Family with Autosomal Dominant Primary Open-Angle Glaucoma. PLoS One 10:e0132529
Hejtmancik, J Fielding; Riazuddin, S Amer; McGreal, Rebecca et al. (2015) Lens Biology and Biochemistry. Prog Mol Biol Transl Sci 134:169-201
Sindhu Kumari, S; Gupta, Neha; Shiels, Alan et al. (2015) Role of Aquaporin 0 in lens biomechanics. Biochem Biophys Res Commun 462:339-45
Mackay, Donna S; Bennett, Thomas M; Culican, Susan M et al. (2014) Exome sequencing identifies novel and recurrent mutations in GJA8 and CRYGD associated with inherited cataract. Hum Genomics 8:19
Lo, Woo-Kuen; Biswas, Sondip K; Brako, Lawrence et al. (2014) Aquaporin-0 targets interlocking domains to control the integrity and transparency of the eye lens. Invest Ophthalmol Vis Sci 55:1202-12

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