Mutations of two genes that encode gap junction proteins that are expressed in the lens (CX46 and CX50) are among the most frequent genetic causes of congenital cataracts. Our previous studies of a variety of cataract-associated connexin mutants (predominantly through expression in Xenopus oocytes or transfected mammalian cell lines) have shown that most of these connexin mutants are not functional (and sometimes act as dominant negative inhibitors of their wild type counterparts). Moreover, many of these mutants exhibit one of two types of abnormal cellular behaviors: (1) they accumulate in cytoplasmic inclusions and appear to be resistant to degradation or (2) they do not traffic properly to the plasma membrane and localize within the secretory pathway. We hypothesize that lens cells expressing mutant connexins that form cytoplasmic inclusions or are retained within the secretory pathway will exhibit unique abnormalities due to abnormal interactions (or lack of interactions) of the connexin mutants with lens-specific proteins causing their retention, altered abundance, or decreased function. Experiments are proposed to study representative members of each class of connexin mutants in lens cells (of chicken embryos, stably transfected lens epithelial cell lines, or lenses of mice carrying connexin mutations). A repertoire of microscopy, cell biological and biochemical approaches will be used to address two central questions: """""""" What are the fates of the mutant connexins in the lens? """""""" What are the consequences of expression of the mutant connexins upon other lens components? The data obtained from these studies are likely to have broad implications towards understanding cataract formation in general, since similar cellular abnormalities (formation of inclusions and retention in the biosynthetic pathway) have also been observed for many other cataract-associated mutant proteins.
Cataracts are the major cause of blindness worldwide and are a major cause of visual impairment in the United States. Mutations of two genes that encode gap junction proteins (CX46 and CX50) that are expressed in the lens are among the most frequent genetic causes of congenital cataracts. Studies are proposed to elucidate the cellular and biochemical basis of cataracts due to these mutant connexins.
| 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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