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X. Gong, L. Li, C. Cheng, T. White, R. Mathias, B. Chang, C.-H. Xia; Gap Junction Mediated Cataract Formation and Prevention. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3182.
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© ARVO (1962-2015); The Authors (2016-present)
To understand the molecular and cellular mechanisms for establishing and maintaining lens transparency. We investigated how disrupted gap junction communication leads to different types of cataracts and how elevated gap junction communication prevents cataracts caused by certain connexin or crystallin gene mutations.
Mutant mouse lines with connexin and gamma-crystallin mutations were characterized by genetic approaches. Cataract severity was quantified by lens light scattering. Histology, immunostaining and western blotting showed morphological and biochemical changes of different mutant lenses. Lens total ions concentrations were measured by a coupled plasma-optical emission spectrometer.
Interactions between α8 (Cx50) mutant alleles (G22R or S50P point mutation) and wild-type α8 and/or α3 (Cx46) wild-type alleles led to distinct cataracts. Mutant α8-S50P allele, not mutant α8-G22R allele, suppressed the elongation of lens primary fiber cells in the presence of α8 wild-type allele. Wild-type α3 alleles interacted with both α8 mutations to disrupt secondary fibers, and both α8 mutant connexins alone did not form functional gap junctions. Interestingly, knockin α3 connexin in the lens could partially restore gap junctions consisting of α8-G22R mutant proteins and alleviate cataract severity. Unexpectedly, knockin α3 connexin also prevented severe nuclear cataracts caused by the γB-crystallin S11R point mutation, which disrupted membrane-skeletal structures and elevated calcium level to initiate calcium-dependent protein degradation. Knockin α3 connexin prevented protein degradation in γB-S11R lenses.
Interactions between α8 mutant and α8 and/or α3 wild-type subunits altered gap junction communication in lens primary and secondary fiber cells to lead to distinct cataracts. The phenotypic rescue of α8-G22R mutant lens by knockin α3 is probably due to an elevated gap junction communication contributed partly by heteromeric channels formed by mutant α8 and wild-type α3 subunits. Elevated gap junction communication via knockin α3 either 1) facilitates calcium efflux to lower calcium concentration thus preventing protease activation in γB-S11R mutant lenses or 2) enhances lens homeostasis to prevent the disruption of membrane-skeletal structures by γB-S11R mutant proteins.
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