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X. Gong, C. Xia, M. Wang, H. Liu, A. Park, N. Hawes, B. Chang; Different Cataracts Caused by Combinatorial Effects of Wildtype and Mutant Forms of Connexins with Other Lens Factor(s) . Invest. Ophthalmol. Vis. Sci. 2004;45(13):4597.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: In order to understand the structural and functional relationship between Gja3Cx46 and Gja8Cx50 connexins and to elucidate molecular mechanism of cataractogenesis, we have carried out a comparison study of cataracts caused by different connexin mutations including three Gja8 point mutations (G22R, S50P and R205G), Gja3 and Gja8 knockouts, and compound mutations generated from the intercrossing of these different mutant lines. We want to identify other lens factor(s) that manifest the severity of cataracts in connexin mutations. Methods: Mouse lenses were analyzed by histology, thin–sectional transmission EM, immunohistochemistry, and western blotting. Gap junction formation was evaluated in culture cells. A genome–wide linkage analysis was used to find the genetic modifier for cataractogenesis in connexin mutations. Results: All three Gja8 point mutations failed to form functional gap junctions both in vivo and in vitro. Altered lens epithelial cells and the swelling of differentiating fibers in Gja8R205 mutation were solely dependent on the presence of endogenous Gja3 based on the fact that these cellular phenotypes were rescued in Gja8 R205 Gja3–/– double mutations. However, lens posterior rupture of Gja8 G22R mutation was unchanged in Gja8 G22R Gja3 –/– double mutation. Gja8 S50P mutation showed the most detrimental effect to the lens among three point mutations. Heterozygous S50P lens was very small and/or ruptured, its eye size reduced almost 50%. The phosphorylated forms of Gja3 were reduced in all Gja8 point mutations. The degree of size reduction in Gja8 mutations corresponded to the abundance of cellular nuclei in the lens and/or posterior rupture. Variable cataracts in connexin mutations seems to be regulated by genetic factors on both Chr 2 and 7. Conclusions: Endogenous wild type Gja3 connexin contribute to the lens distinctive phenotypes of Gja8 point mutations, and it acts differently in each Gja8 point mutation that perturbs fiber differentiation. Gja8 and Gja3 interact each other via a co–regulation by phosphorylation. We hypothesize that Gja8 and/or Gja3 interact with other lens proteins to form an intrigue network to maintain lens homeostasis and different connexin mutations selectively disrupt a subset function of this network to cause unique cataracts.
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