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Rosanne M. Yetemian, Shun-Ping Huang, Bruce M. Brown, Guey Shuang Wu, Cheryl M. Craft; Susceptibility Modifiers Contribute to Phenotype Variability in Mouse Arrestin1 Knockout Cone Dystrophy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):78.
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© ARVO (1962-2015); The Authors (2016-present)
Our study focuses on identifying susceptibility modulators involved in the variable Arrestin1 (Arr1)-/- cone dystrophy phenotype. Arr1 contributes to photoreceptor recovery & light adaptation by binding to phosphorylated opsins & interacting with N-ethylmaleimide sensitive factor (NSF). In humans, ARR1 genetic defects lead to Oguchi Disease; in mice, Arr1-/-A have light-dependent retinal degeneration (Chen et al. 1999 IOVS 40:2978) and light-independent cone dystrophy (Arr1-/-B)(Brown et al. 2010 IOVS 51:2372). Light-independent photoreceptor cell death was significanly lower at postnatal day (P)60 in the Arr1-/-A compared to Arr1-/-B.
Differential retinal proteomic and genomic expression patterns were examined between founder colony, Arr1-/-A (J. Chen, USC), and Arr1-/-B with EttanTM DIGE, mass spectroscopy (MS), IEF-immunoblot, & allelic specific PCR (ASPCR) analysis. Deregulated retinal transcripts identified with Affymetrix exon array were analyzed using Ingenuity Pathway Analysis (IPA), then verified with quantitative RT-PCR, immunoblot, & immunohistochemistry analysis at P30 & P60.
Two Peroxiredoxin 6 (Prdx6) proteomic isoforms (pH 6.12 & 5.7), a thiol-specific antioxidant enzyme with PLA2 activity known to differentially regulate reactive oxygen species, were identified by MS, then Prdx6 genomic ASPCR and retinal transcripts verified a SNP(A/C) coding an amino acid variant (A122D): Arr1-/-A has 129SvJ acidic Prdx6 (122D), while Arr1-/-B has C57Bl/6J basic (122A) isoform. Arr1-/-B compared to either control or Arr1-/-A retinal transcripts were significantly up-regulated with enhanced protein expression, including 7 Complement components, Annexin1A, Endothelin2, Oncostatin M receptor, STAT3, SOCS3, & GFAP.
The susceptibility of Arr1-/-B to light-independent cone dystrophy is a multi-step, complex network linked initially to an acute phase response signaling activation of the Complement System, which is also implicated in the pathogenesis of age-related macular degeneration (AMD). This pathway may be epigenetically protecting Arr1-/-A photoreceptors with the expression of the resistant Prdx6 isoform, which is associated with reduced susceptibility for oxidative damage. Our data links other genes working in concert with Prdx6 that may lead to retinal degeneration susceptibility in other eye diseases, which may provide novel therapeutic approaches for treatment.
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