Cargando…

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

PURPOSE: 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. METHODS:...

Descripción completa

Detalles Bibliográficos
Autores principales: Tang, Peter H., Velez, Gabriel, Tsang, Stephen H., Bassuk, Alexander G., Mahajan, Vinit B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Association for Research in Vision and Ophthalmology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735613/
https://www.ncbi.nlm.nih.gov/pubmed/30657523
http://dx.doi.org/10.1167/iovs.18-25624
_version_ 1783450379868962816
author Tang, Peter H.
Velez, Gabriel
Tsang, Stephen H.
Bassuk, Alexander G.
Mahajan, Vinit B.
author_facet Tang, Peter H.
Velez, Gabriel
Tsang, Stephen H.
Bassuk, Alexander G.
Mahajan, Vinit B.
author_sort Tang, Peter H.
collection PubMed
description PURPOSE: 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. METHODS: A retrospective chart review, human eye histopathology, Sanger DNA sequencing, protein structural modeling, and in vitro proteolysis assays were performed. RESULTS: 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. CONCLUSIONS: 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.
format Online
Article
Text
id pubmed-6735613
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher The Association for Research in Vision and Ophthalmology
record_format MEDLINE/PubMed
spelling pubmed-67356132019-09-20 VCAN Canonical Splice Site Mutation is Associated With Vitreoretinal Degeneration and Disrupts an MMP Proteolytic Site Tang, Peter H. Velez, Gabriel Tsang, Stephen H. Bassuk, Alexander G. Mahajan, Vinit B. Invest Ophthalmol Vis Sci Retina PURPOSE: 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. METHODS: A retrospective chart review, human eye histopathology, Sanger DNA sequencing, protein structural modeling, and in vitro proteolysis assays were performed. RESULTS: 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. CONCLUSIONS: 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. The Association for Research in Vision and Ophthalmology 2019-01 /pmc/articles/PMC6735613/ /pubmed/30657523 http://dx.doi.org/10.1167/iovs.18-25624 Text en Copyright 2019 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
spellingShingle Retina
Tang, Peter H.
Velez, Gabriel
Tsang, Stephen H.
Bassuk, Alexander G.
Mahajan, Vinit B.
VCAN Canonical Splice Site Mutation is Associated With Vitreoretinal Degeneration and Disrupts an MMP Proteolytic Site
title VCAN Canonical Splice Site Mutation is Associated With Vitreoretinal Degeneration and Disrupts an MMP Proteolytic Site
title_full VCAN Canonical Splice Site Mutation is Associated With Vitreoretinal Degeneration and Disrupts an MMP Proteolytic Site
title_fullStr VCAN Canonical Splice Site Mutation is Associated With Vitreoretinal Degeneration and Disrupts an MMP Proteolytic Site
title_full_unstemmed VCAN Canonical Splice Site Mutation is Associated With Vitreoretinal Degeneration and Disrupts an MMP Proteolytic Site
title_short VCAN Canonical Splice Site Mutation is Associated With Vitreoretinal Degeneration and Disrupts an MMP Proteolytic Site
title_sort vcan canonical splice site mutation is associated with vitreoretinal degeneration and disrupts an mmp proteolytic site
topic Retina
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735613/
https://www.ncbi.nlm.nih.gov/pubmed/30657523
http://dx.doi.org/10.1167/iovs.18-25624
work_keys_str_mv AT tangpeterh vcancanonicalsplicesitemutationisassociatedwithvitreoretinaldegenerationanddisruptsanmmpproteolyticsite
AT velezgabriel vcancanonicalsplicesitemutationisassociatedwithvitreoretinaldegenerationanddisruptsanmmpproteolyticsite
AT tsangstephenh vcancanonicalsplicesitemutationisassociatedwithvitreoretinaldegenerationanddisruptsanmmpproteolyticsite
AT bassukalexanderg vcancanonicalsplicesitemutationisassociatedwithvitreoretinaldegenerationanddisruptsanmmpproteolyticsite
AT mahajanvinitb vcancanonicalsplicesitemutationisassociatedwithvitreoretinaldegenerationanddisruptsanmmpproteolyticsite