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B.S. Lee, S. Kameya, R.S. Smith, W. Hicks, J. Hsu, N.S. Peachey, J.K. Naggert, P.M. Nishina; Effects of Large Gene Mutation in the Veils Mouse Retina . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1650.
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Purpose: Large encodes for a putative glycosyltransferase whose only known substrate is alpha–dystroglycan, a component of the dystrophin glycoprotein complex (DGC). Mutations in DGC components are known to cause human disorders including muscular dystrophies, and ocular and other brain related abnormalities. The veils mutant (Largevls) is a remutation of Largemyd. Both mutations show very similar phenotypes. Effects of the Largemyd mutation in mouse muscle and brain have been well documented. There is, however, little information on the effects of either Large gene mutations on the retina. Here we report a comprehensive characterization of retinal abnormalities in both Largevls and Largemyd mutant mice. Methods: Retinal structure was studied using light and electron microscopy (EM) and immunohistochemistry. Retinal function was assessed using electroretinograms (ERGs) recorded under dark– and light– adapted conditions. Results obtained from Large mutants were compared to unaffected control littermates. Results: In both Largevls and Largemyd mice, the inner limiting membrane (ILM) is disrupted and ganglion cells are displaced ectopically into the vitreous. In both mutants, there is an age–related loss of cells in the peripheral retina. Unlike muscle, most components of DGC were significantly reduced in the ILM. In the outer plexiform layer (OPL), however, the DGC is intact although beta–dystroglycan expression is reduced. At the EM level, the integrity of the OPL in Large mutant mice was compromised and synaptic complexes were missing or disrupted. Under all stimulus conditions, the ERG b–wave was dramatically slowed and reduced in amplitude in both Largevls and Largemyd mice. Conclusions: The results indicate that mutations in Large cause a number of retinal abnormalities and indicate that proper glycosylation of alpha–dystroglycan is important for maintaining the structural and functional integrity of the mouse retina. It remains to be determined whether normal DGCs are never formed or if they are formed and then rapidly degraded. In either case, EM and ERG data indicate that alpha–dystroglycan and other DGC components are required to form and maintain ribbon synapses in the OPL. Differences between muscle and retina indicate that components of DGC may be regulated differently in the retina.
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