The eye lens not only provides and excellent model system for development, aging, and protein structure and interaction, but is important clinically for vision. A better understanding of cataractogenesis will come through an understanding of the molecular components of the lens of the eye and the ways in which lesions of these components are manifested, structurally and functionally, as opacity of the lens. Currently, several different genetic congenital cataracts are being studied by linkage analysis, physical mapping, mutational screening, and expression in transgenic mice and in vitro. In addition, it is apparent that hereditary lesions that mimic or contribute additively to environmental stress known to cause cataracts might be candidate genes for causing age related cataracts. Age related cataracts are being studied by association analysis and sequencing of candidate genes followed by molecular genetic investigation of wild type and mutant gene structure and function. The work in this project is designed to specifically concentrate on congenital and complex hereditary cataracts and to take full advantage of molecular technology developed for linkage analysis and protein structural and functional studies. Lens crystallins comprise over 90% of the soluble protein of the lens and are heavily modified in most cataracts. The effects that specific modifications of beta and gamma-crystallin structure produce on crystallin functions, such as stability and formation of macromolecular aggregates, are being studied using SF9 cells or bacteria transformed with coding sequences of normal and modified beta A3/A1-, B1, B2- and gammaS-crystallin genes. Regions of the beta-crystallin molecule of special interest include the amino and carboxy terminal arms, the connecting peptide and the Greek key motifs of the core domains. In addition, new loci and genes associated with age related cataract are being identified, and the characteristics of mutations leading to congenital Mendelian or age related complex cataracts are being studied. Finally, the biological activity of crystallins in extralenticular systems are being investigated.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAEY000281-21
Application #
8737613
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
2013
Total Cost
$775,365
Indirect Cost
Name
U.S. National Eye Institute
Department
Type
DUNS #
City
State
Country
Zip Code
Jiao, Xiaodong; Kabir, Firoz; Irum, Bushra et al. (2016) A Common Ancestral Mutation in CRYBB3 Identified in Multiple Consanguineous Families with Congenital Cataracts. PLoS One 11:e0157005
Ma, Xiaoyin; Jiao, Xiaodong; Ma, Zhiwei et al. (2016) Polymorphism rs7278468 is associated with Age-related cataract through decreasing transcriptional activity of the CRYAA promoter. Sci Rep 6:23206
Boone, Philip M; Yuan, Bo; Gu, Shen et al. (2016) Hutterite-type cataract maps to chromosome 6p21.32-p21.31, cosegregates with a homozygous mutation in LEMD2, and is associated with sudden cardiac death. Mol Genet Genomic Med 4:77-94
Khan, Shahid Y; Vasanth, Shivakumar; Kabir, Firoz et al. (2016) FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1. Nat Commun 7:10953
Shiels, Alan; Hejtmancik, J Fielding (2016) Mutations and mechanisms in congenital and age-related cataracts. Exp Eye Res :
Ma, Zhiwei; Yao, Wenliang; Chan, Chi-Chao et al. (2016) Human βA3/A1-crystallin splicing mutation causes cataracts by activating the unfolded protein response and inducing apoptosis in differentiating lens fiber cells. Biochim Biophys Acta 1862:1214-27
Hejtmancik, J Fielding; Riazuddin, S Amer; McGreal, Rebecca et al. (2015) Lens Biology and Biochemistry. Prog Mol Biol Transl Sci 134:169-201
Hejtmancik, J Fielding (2015) Ophthalmology: Cataracts dissolved. Nature 523:540-1
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

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