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L. Li, B. Chang, C. Cheng, N. L. Hawes, C.-H. Xia, X. Gong; GammaB-Crystallin Mutation Causes Severe Nuclear Cataracts by Disrupting Membrane-Cytoskeletal Structures of Inner Lens Fiber Cells. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2044.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the molecular and cellular mechanisms for how the γB-crystallin S11R mutation leads to dense nuclear cataracts. We further compared the mechanistic differences between γB-S11R and γB-I4F mutations that lead to distinct cataracts.
A genome-wide linkage analysis and DNA sequencing confirmed a point mutation of the γB-crystallin gene in a dominant cataractous mouse line. Lens phenotypes were characterized by histology, western blotting and immunohistochemistry assays. Lens total ions concentrations were measured by a coupled plasma-optical emission spectrometer (ICP-OES). The properties of γB mutant proteins were further examined and compared to those of wild-type proteins in transfected culture cells.
A substitution of A to C in the γB-crystallin gene, which results in the expression of γB-S11R mutant proteins, caused dominant cataracts. Homozygous mutant mice developed nuclear cataracts associated with disrupted inner lens fiber cells and enlarged extracellular spaces. Immunohistochemsitry data revealed that γ-crystallin aggregates associated with plasma membrane of inner mature fiber cells and disrupted actin filaments. Western blotting data suggested increased calcium-dependent degradation of crystallin proteins. ICP-OES confirmed an elevation of calcium concentration in homozygous mutant lenses. Unlike γB-I4F mutant proteins that formed intracellular aggregates in transfected cells, γB-S11R mutant proteins did not.
These data suggest that γB-S11R mutant proteins form membrane-associated aggregates to disrupt the plasma membranes and actin filaments of inner fiber cells. Damaged plasma membranes allow extracellular calcium to enter into fiber cells thus leading to increased intracellular calcium levels. Elevated intracellular calcium concentration activates calcium-dependent proteases, such as calpains, to degrade crystallin proteins and other lens proteins leading to severe nuclear cataracts. Unlike γB-I4F mutant proteins that are unstable and form intracellular aggregates to cause a lamellar cataract, γB-S11R mutant proteins specifically disrupt the plasma membranes and/or actin filaments of inner fiber cells to trigger calcium-dependent protein degradation to cause a dense nuclear cataract.
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