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      VCAN Canonical Splice Site Mutation is Associated With Vitreoretinal Degeneration and Disrupts an MMP Proteolytic Site


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          To gain insight into the pathophysiology of vitreoretinal degeneration, the clinical course of three family members with Versican Vitreoretinopathy (VVR) is described, and a canonical splice site mutation in the gene encoding for versican ( VCAN) protein was biochemically analyzed.


          A retrospective chart review, human eye histopathology, Sanger DNA sequencing, protein structural modeling, and in vitro proteolysis assays were performed.


          The proband (II:1), mother (I:2), and younger sibling (II:2) suffered retinal degeneration with foveal sparing and retinal detachments with proliferative vitreoretinopathy, features that were confirmed on histopathologic analysis. All affected members carried a heterozygous adenine to guanine variant (c.4004-2A>G) predicted to result in exon 8 skipping or the deletion of 13 amino acids at the beginning of the GAGβ chain (VCAN p.1335-1347). This deleted region corresponded to a putative MMP cleavage site, validated using fluorescence resonance energy transfer (FRET)-based proteolysis assays. Proteomic network analysis identified 10 interacting partners in the human vitreous and retina linked to retinal detachment and degeneration.


          VVR causes significant ocular disease, including retinal detachment and retinal dystrophy. The intronic VCAN mutation removes an MMP cleavage site, which alters versican structure and results in abnormal vitreous modeling. Disruption of a versican protein network may underlie clinicopathologic disease features and point to targeted therapies.

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          Most cited references53

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          MEROPS: the peptidase database

          Peptidases, their substrates and inhibitors are of great relevance to biology, medicine and biotechnology. The MEROPS database (http://merops.sanger.ac.uk) aims to fulfil the need for an integrated source of information about these. The database has a hierarchical classification in which homologous sets of peptidases and protein inhibitors are grouped into protein species, which are grouped into families, which are in turn grouped into clans. The classification framework is used for attaching information at each level. An important focus of the database has become distinguishing one peptidase from another through identifying the specificity of the peptidase in terms of where it will cleave substrates and with which inhibitors it will interact. We have collected over 39 000 known cleavage sites in proteins, peptides and synthetic substrates. These allow us to display peptidase specificity and alignments of protein substrates to give an indication of how well a cleavage site is conserved, and thus its probable physiological relevance. While the number of new peptidase families and clans has only grown slowly the number of complete genomes has greatly increased. This has allowed us to add an analysis tool to the relevant species pages to show significant gains and losses of peptidase genes relative to related species.
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            Versican: a versatile extracellular matrix proteoglycan in cell biology.

            Versican is a large extracellular matrix proteoglycan that is present in a variety of tissues. Successful cloning of the gene in man, mouse, cow and chicken has revealed the existence of at least four splice variants of versican, which differ in the size of the core protein and the number of glycosaminoglycan chains. The highly interactive nature of versican provides a basis for its importance as a structural molecule, creating loose and hydrated matrices during key events in development and disease; and by interacting either directly with cells or indirectly with molecules that associate with cells to, in part, regulate cell adhesion and survival, cell proliferation, cell migration and extracellular matrix assembly. Several studies within the past two years have confirmed a significant role for versican in regulating cell phenotype.
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              Proteoglycans as modulators of growth factor activities.


                Author and article information

                Invest Ophthalmol Vis Sci
                Invest. Ophthalmol. Vis. Sci
                Invest Ophthalmol Vis Sci
                Investigative Ophthalmology & Visual Science
                The Association for Research in Vision and Ophthalmology
                January 2019
                : 60
                : 1
                : 282-293
                [1 ]Byers Eye Institute, Omics Laboratory, Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, California, United States
                [2 ]Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States
                [3 ]Medical Scientist Training Program, University of Iowa, Iowa City, Iowa, United States
                [4 ]Bernard and Shirlee Brown Glaucoma Laboratory, Department of Pathology and Cell Biology, Department of Ophthalmology, College of Physicians and Surgeons, Columbia University, New York, New York, United States
                [5 ]Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States
                Author notes
                Correspondence: Vinit B. Mahajan, Omics Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94304, USA; vinit.mahajan@ 123456stanford.com .

                PHT and GV are joint first authors.

                iovs-60-01-09 IOVS-18-25624R2
                Copyright 2019 The Authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

                : 31 August 2018
                : 29 November 2018

                versican,wagner disease,erosive vitreoretinopathy,vcan,genetics,mmp-2,mmp-9,gelatinase,extracellular matrix,vitreous,retinal detachment


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