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M. G. Schmidt, M. T. Budak, U. Basu, C. H. Mitchell, T. S. Khurana; Differential Distribution of Utrophin A & B Promoter Products in Mouse Retina. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3061.
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© ARVO (1962-2015); The Authors (2016-present)
Duchenne's Muscular Dystrophy (DMD) patients have dystrophin mutations associated with muscle and CNS defects including mental retardation and ERG abnormalities. Deficiency of dystrophin, its fetal isoform & autosomal homolog Utrophin (Utrn), and/or complexed proteins resulting in impaired clustering of Kir4.1 and aquaporin-4 in Müller cells are thought to underlie retinal dysfunction. Utrn promoter activation-mediated upregulation can functionally substitute for dystrophin in vivo and offers a potential therapeutic strategy. However, knowledge of which Utrn promoter to target is currently unknown since previously promoter specific reagents were unavailable. The present study uses novel reagents to address differential expression of the Utrn promoter A and B products in retina.
A novel Taqman assay and exon-specific antibodies were generated to unequivocally detect Utrn A&B promoter products in murine retina using qPCR, immunohistochemistry and confocal microscopy.
Utrn A&B mRNAs are expressed in whole retina. Immunocytochemical studies reveal spatial differences in promoter product distribution. Utrn A&B are expressed in Müller cells at the outer limiting membrane; however, Utrn A localizes to the inner limiting membrane and inner plexiform layer whilst Utrn B localizes to the ganglion cell layer. Additionally, Utrn A labeled cone outer segments.
We demonstrate that Utrn A&B products are present in retina, though expression is promoter-dependent and spatially restricted. Targeting either promoter would suffice to upregulate Müller cell Utrn and is predicted to correct impaired Kir4.1 and aquaporin-4 clustering. Localization of Utrn A to cones and the subtle color perception abnormalities reported in DMD patients (Costa et al. IOVS E-Abstract 3700; 2006) suggest a physiological role for the dystrophin complex in color vision.
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