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      Retbindin: A riboflavin Binding Protein, Is Critical for Photoreceptor Homeostasis and Survival in Models of Retinal Degeneration

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          Abstract

          The large number of inherited retinal disease genes (IRD), including the photopigment rhodopsin and the photoreceptor outer segment (OS) structural component peripherin 2 (PRPH2), has prompted interest in identifying common cellular mechanisms involved in degeneration. Although metabolic dysregulation has been shown to play an important role in the progression of the disease etiology, identifying a common regulator that can preserve the metabolic ecosystem is needed for future development of neuroprotective treatments. Here, we investigated whether retbindin (RTBDN), a rod-specific protein with riboflavin binding capability, and a regulator of riboflavin-derived cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), is protective to the retina in different IRD models; one carrying the P23H mutation in rhodopsin (which causes retinitis pigmentosa) and one carrying the Y141C mutation in Prph2 (which causes a blended cone-rod dystrophy). RTBDN levels are significantly upregulated in both the rhodopsin ( Rho) P23H/+ and Prph2 Y141C/+ retinas. Rod and cone structural and functional degeneration worsened in models lacking RTBDN. In addition, removing Rtbdn worsened other phenotypes, such as fundus flecking. Retinal flavin levels were reduced in Rho P23H/+/Rtbdn −/− and Prph2 Y141C/+/Rtbdn −/− retinas. Overall, these findings suggest that RTBDN may play a protective role during retinal degenerations that occur at varying rates and due to varying disease mechanisms.

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          Most cited references49

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          Retinitis pigmentosa.

          Hereditary degenerations of the human retina are genetically heterogeneous, with well over 100 genes implicated so far. This Seminar focuses on the subset of diseases called retinitis pigmentosa, in which patients typically lose night vision in adolescence, side vision in young adulthood, and central vision in later life because of progressive loss of rod and cone photoreceptor cells. Measures of retinal function, such as the electroretinogram, show that photoreceptor function is diminished generally many years before symptomic night blindness, visual-field scotomas, or decreased visual acuity arise. More than 45 genes for retinitis pigmentosa have been identified. These genes account for only about 60% of all patients; the remainder have defects in as yet unidentified genes. Findings of controlled trials indicate that nutritional interventions, including vitamin A palmitate and omega-3-rich fish, slow progression of disease in many patients. Imminent treatments for retinitis pigmentosa are greatly anticipated, especially for genetically defined subsets of patients, because of newly identified genes, growing knowledge of affected biochemical pathways, and development of animal models.
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            Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa.

            Night blindness is an early symptom of retinitis pigmentosa. The rod photoreceptors are responsible for night vision and use rhodopsin as the photosensitive pigment. We found three mutations in the human rhodopsin gene; each occurred exclusively in the affected members of some families with autosomal dominant retinitis pigmentosa. Two mutations were C-to-T transitions involving separate nucleotides of codon 347; the third was a C-to-G transversion in codon 58. Each mutation corresponded to a change in one amino acid residue in the rhodopsin molecule. None of these mutations were found in 106 unrelated normal subjects who served as controls. When the incidence of these three mutations was added to that of a previously reported mutation involving codon 23, 27 of 150 unrelated patients with autosomal dominant retinitis pigmentosa (18 percent) were found to carry one of these four defects in the rhodopsin gene. All 27 patients had abnormal rod function on monitoring of their electroretinograms. It appears that patients with the mutation involving codon 23 probably descend from a single ancestor. In some patients with autosomal dominant retinitis pigmentosa, the disease is caused by one of a variety of mutations of the rhodopsin gene.
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              Riboflavin (vitamin B-2) and health.

              Riboflavin is unique among the water-soluble vitamins in that milk and dairy products make the greatest contribution to its intake in Western diets. Meat and fish are also good sources of riboflavin, and certain fruit and vegetables, especially dark-green vegetables, contain reasonably high concentrations. Biochemical signs of depletion arise within only a few days of dietary deprivation. Poor riboflavin status in Western countries seems to be of most concern for the elderly and adolescents, despite the diversity of riboflavin-rich foods available. However, discrepancies between dietary intake data and biochemical data suggest either that requirements are higher than hitherto thought or that biochemical thresholds for deficiency are inappropriate. This article reviews current evidence that diets low in riboflavin present specific health risks. There is reasonably good evidence that poor riboflavin status interferes with iron handling and contributes to the etiology of anemia when iron intakes are low. Various mechanisms for this have been proposed, including effects on the gastrointestinal tract that might compromise the handling of other nutrients. Riboflavin deficiency has been implicated as a risk factor for cancer, although this has not been satisfactorily established in humans. Current interest is focused on the role that riboflavin plays in determining circulating concentrations of homocysteine, a risk factor for cardiovascular disease. Other mechanisms have been proposed for a protective role of riboflavin in ischemia reperfusion injury; this requires further study. Riboflavin deficiency may exert some of its effects by reducing the metabolism of other B vitamins, notably folate and vitamin B-6.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                29 October 2020
                November 2020
                : 21
                : 21
                : 8083
                Affiliations
                [1 ]Department of Biomedical Engineering, University of Houston, Houston, TX 77204, USA; amgenc@ 123456Central.UH.EDU (A.M.G.); msmakia@ 123456Central.UH.EDU (M.S.M.); Tirthankar.Sinha@ 123456uth.tmc.edu (T.S.)
                [2 ]Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Shannon-Conley@ 123456ouhsc.edu
                [3 ]Oklahoma Center for Neurosciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
                [4 ]College of Optometry, University of Houston, Houston, TX 77204, USA
                [5 ]Department of Biology and Biochemistry, University of Houston, TX 77204, USA
                Author notes
                [* ]Correspondence: malubaid@ 123456central.uh.edu (M.R.A.-U.); mnaash@ 123456central.uh.edu (M.I.N.); Tel.: +1-713-743-1651 (M.R.A.-U. & M.I.N.); Fax: +1-713-743-0226 (M.R.A.-U. & M.I.N.)
                Author information
                https://orcid.org/0000-0003-3194-3274
                https://orcid.org/0000-0002-7138-0907
                Article
                ijms-21-08083
                10.3390/ijms21218083
                7662319
                33138244
                78a08783-edb0-4556-a79a-8e56fd549cf1
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 30 September 2020
                : 23 October 2020
                Categories
                Article

                Molecular biology
                prph2,retinal degeneration,inherited retinal degeneration,riboflavin,metabolism,flavoproteins,rhodopsin

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