Inherited cataract is a sight-threatening lens disease that usually presents as a congenital, autosomal dominant Mendelian trait showing high penetrance and considerable inter- and intra-familial clinical variation. The primary objective of this project is to determine whether mutations in the genes for connexin50 (Cx50) and connexin46 (CX46) underlie autosomal dominant forms of zonular pulverulent cataract that the PI has mapped to human chromosomes 1q and 13q, respectively. DNA cloning and sequencing techniques will be used to identify mutations and engineer constructs for functional expression studies on the wild-type and mutant forms of Cx50 and Cx46. The voltage-gating properties of wild-type and mutant forms Cx50 and Cx46 synthesized in Xenopus oocytes will be determined using a two microelectrode voltage clamp technique under defined pH conditions. The intercellular channel properties of wildtype and mutant forms Cx50 and Cx46 expressed in the connexin-deficient HeLa cell-line will be measured by fluorescent dye-transfer methods. Transgenic mouse techniques will be used to model the allelic interactions of wild-type and mutant forms of Cx50 and Cx46 that lead to cataract development in the living lens. Results from these studies will help to elucidate the pathogenetic mechanisms underlying a clinically important form of inherited cataract in humans and provide new insight into the role of connexins in human lens development. Ultimately, such data will contribute to the design of new preventative and therapeutic strategies for the clinical management of cataract.
| 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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