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R. G. Schmidt-Kastner, J. Blanks, B. Lorenz, M. Preising; Annotation of Retinal Disease Genes for Regulation by Oxygenation Using Data-Mining of Microarray Studies. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1681.
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© ARVO (1962-2015); The Authors (2016-present)
Oxygenation is variable in the retina due to its light-dependent energy expeditures. In retinal disorders, interactions between mutations and variable oxygenation could contribute to variable clinical manifestation if the affected gene responds to hypoxia. We previously used a database of ischemia-hypoxia response (IHR) genes of the brain to propose oxygen-dependent regulation of widely expressed RP genes (Schmidt-Kastner et al., Mol Vis 2008). We now generated a combined dataset of IHR genes from brain and retina to annotate disease genes for retinal dystrophies, photoreceptor dysfunction and age-related macular degeneration (AMD).
Genes for retinal dystrophies and photoreceptor dysfunction were compiled from NEIBank, RISN, and RetNet. Genes reproducibly associated with the risk of AMD were identified in the HuGE Navigator. IHR genes of the retina were compiled from five microarray studies and combined with the brain-derived IHR gene dataset. Intersections between datasets defined retinal disease genes responding to ischemia-hypoxia (i.e. oxygenation).
Several genes associated with monogenic retinal disease were identified as regulated by ischemia-hypoxia, i.e. BBS2, BBS10, CHM, CNGA1/RP42, CNGA3, CNGB1/RP45, EFEMP1/DHRD, KCNJ13/SVD, LRAT, PROM1/RP41, RDH5, RGR/RP44, SEMA4/RP35, Unc119-HRG4, TIMP3/SFD, and TTC8/BBS8. Susceptibility genes for AMD matched with IHR genes, i.e. APOE, C3, CFH, EPHX1, FBLN5, HTRA1, PON1, SERPING1, SOD2, TLR4, VEGF, VLDLR (12/46 studied; chi-square test p<0.01).
Regulation by oxygenation could lead to unstable expression levels for matched genes underlying retinal dystrophies and photoreceptor dysfunction. Multiple susceptibility genes in AMD are associated with ischemia-hypoxia responses, supporting the role of hypoxia in the pathophysiology. To what extent physiological variations in retinal oxygenation during light/dark cycles are sufficient to induce instability of expression remains to be examined.
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