The survival and transparency of the lens depend on intercellular communication through lens fiber gap junction channels formed of two connexins, Cx46 and Cx50. Families have been identified with inherited cataracts associated with mutations of both of these connexins. We have established transfected cell and transgenic mouse expression systems for the study of normal and mutated lens connexins. Our recent studies show that the cloned human mutant connexins do not make functional gap junction channels. Moreover, in stably transfected cells, our data regarding fiber connexin mutants (including Cx50P88S, Cx46fs380, and Cx50P88Q) show that they do not properly assemble into gap junctions, because they are retained in the cytoplasm (at different sites) and are not properly degraded. This project will focus on testing the central question: How do perturbations of gap junctions (especially mutation of the fiber connexins) affect lens development, structure, and function? We will use immuno- and bio-chemical techniques to examine the cellular processing of Cx50P88S, Cx46fs380, and other connexin mutants in stably transfected cells to ask: What are the cellular mechanisms and consequences of the abnormal trafficking and accumulation of cataract-associated mutant connexins? (Aim 1) We will develop and analyze transgenic mice that express the wild-type human Cx50 and ES cell-derived mice that express the mutant, Cx46fs380. We will use them to ask: Can the pathogenesis of human cataracts due to over-expression of a wild-type connexin or due to expression of a mutant connexin be elucidated in mouse models? Do the lenses of these mice exhibit alterations of connexin distribution/trafficking and function similar to those seen in transfected cells? What are the consequences of expression of Cx46fs380 upon lens membranes, intercellular communication, other lens components and transparency? (Aim 2) These studies will elucidate the pathogenesis of cataracts and the importance of lens fiber connexins for maintaining lens transparency.
| Jara, Oscar; Minogue, Peter J; Berthoud, Viviana M et al. (2018) Chemical chaperone treatment improves levels and distributions of connexins in Cx50D47A mouse lenses. Exp Eye Res 175:192-198 |
| Gao, Junyuan; Minogue, Peter J; Beyer, Eric C et al. (2018) Disruption of the lens circulation causes calcium accumulation and precipitates in connexin mutant mice. Am J Physiol Cell Physiol 314:C492-C503 |
| Beyer, Eric C; Berthoud, Viviana M (2018) Gap junction gene and protein families: Connexins, innexins, and pannexins. Biochim Biophys Acta Biomembr 1860:5-8 |
| Leybaert, Luc; Lampe, Paul D; Dhein, Stefan et al. (2017) Connexins in Cardiovascular and Neurovascular Health and Disease: Pharmacological Implications. Pharmacol Rev 69:396-478 |
| Minogue, Peter J; Gao, Junyuan; Zoltoski, Rebecca K et al. (2017) Physiological and Optical Alterations Precede the Appearance of Cataracts in Cx46fs380 Mice. Invest Ophthalmol Vis Sci 58:4366–4374 |
| Beyer, Eric C; Berthoud, Viviana M (2017) Gap junction structure: unraveled, but not fully revealed. F1000Res 6:568 |
| Berthoud, Viviana M; Ngezahayo, Anaclet (2017) Focus on lens connexins. BMC Cell Biol 18:6 |
| Kuo, Debbie S; Sokol, Jared T; Minogue, Peter J et al. (2017) Characterization of a variant of gap junction protein ?8 identified in a family with hereditary cataract. PLoS One 12:e0183438 |
| Berthoud, Viviana M; Minogue, Peter J; Snabb, Joseph I et al. (2016) Connexin23 deletion does not affect lens transparency. Exp Eye Res 146:283-8 |
| Senthil Kumar, G; Dinesh Kumar, K; Minogue, P J et al. (2016) The E368Q Mutant Allele of GJA8 is Associated with Congenital Cataracts with Intrafamilial Variation in a South Indian Family. Open Access J Ophthalmol 1: |
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