The crystalline lens plays a central role in vertebrate anterior eye development and refractive vision. Loss of lens transparency, or cataract(s), is a clinically important cause of low vision that despite surgical treatment remains a leading cause (~40%) of blindness worldwide. Typically, cataract is acquired with aging (>40 yrs) as a multi-factorial or complex disorder involving environmental and genetic risk factors. In addition, cataract may be inherited as a Mendelian disorder usually with juvenile-onset, and many mouse models of human cataract have been described. While several environmental risk factors have been established for age-related cataract, little is known about the nature and precise role of genetic factors that are estimated to account for ~50% of the risk. However, there is increasing evidence that genes underlying inherited forms of cataract are also involved in age-related cataract. The overall goal of this research is to advance understanding of the molecular mechanisms/pathways that lead to cataract. Specifically, we propose to identify novel genes for inherited forms of cataract in humans, and to identify the causative gene in a mouse model of human age-related cataract using a combination of molecular genetic and genomic techniques. Results from these studies will provide new insights about the molecular basis of lens development, aging and cataractogenesis, and ultimately may contribute to the discovery of non-surgical means to delay, reverse or even prevent cataract formation.

Public Health Relevance

Age-related cataract afflicts more than 20 million of the US population over age 40 (~17%), and despite increasing direct medical costs for surgical treatment, is the leading cause of low vision. Congenital and infantile forms of cataract are also a significant cause of visual impairment in childhood, and surgical management of pediatric cataract is susceptible to post-operative complications including, posterior capsular opacification, aphakic glaucoma or ocular hypertension, eye movement disorders (nystagmus, strabismus, amblyopia), uveitis and retinal detachment. This research aims to advance understanding of the molecular genetic mechanisms that cause cataract, and contribute to the discovery of alternative non-surgical treatments for cataract.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Araj, Houmam H
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Washington University
Schools of Medicine
Saint Louis
United States
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Shiels, Alan; Hejtmancik, J Fielding (2017) Mutations and mechanisms in congenital and age-related cataracts. Exp Eye Res 156:95-102
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

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