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Muayyad R Al-Ubaidi, Ryan Kelley, Jianhai Du, James Hurley, Muna I Naash; Ablation of Retbindin Alters Flavin Levels and Leads to Rod and Cone Photoreceptor Degeneration. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Retbindin (Retb) is a retina-specific protein that localizes extracellularly at the outer segment/retinal pigment epithelium interface and is capable of binding riboflavin in vitro. Since riboflavin and its derivatives [flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD)] are co-factors involved in regulating metabolic enzymes activities, we hypothesize that Retb is involved in binding/transport of flavins and its absence will lead to deleterious metabolic alterations.
Methods: A knockout mouse (Retb-/-) was generated in which the coding sequence was replaced with eGFP. Developmental structural, functional and biochemical analyses were performed. Flavin levels were measured with HPLC while metabolites were quantified by LC-MS and data was analyzed using MetaboAnalyst 3.0.
Results: Expression of eGFP in Retb-/- mice was restricted to rod photoreceptors, consistent with the distribution of Retb in WT retinas. Retb-/- retinas contained significantly reduced levels of flavins and exhibited age- and dose-dependent decline, associated with cell loss, in both rod and cone functions as early as postnatal day 120. We also observed significant reductions in the binding affinity of Retb-/- retinas to C14-labeled riboflavin. Finally, a metabolomic analysis revealed that elimination of Retb led to changes in glycolysis, TCA cycle and in amino acid metabolism.
Conclusion: Our results are consistent with our hypothesis and Retb. Further investigation into the role of Retb in the retina is needed to determine the exact metabolic changes leading to the degeneration and to determine the role of specific pathways in the degenerative process in patients with mutations in proteins other than retbindin. This will enable us to determine the commonality of the metabolic changes to retinal degenerative diseases.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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