Journal article
VCAN Canonical Splice Site Mutation is Associated With Vitreoretinal Degeneration and Disrupts an MMP Proteolytic Site
Investigative ophthalmology & visual science, Vol.60(1), pp.282-293
01/02/2019
DOI: 10.1167/iovs.18-25624
PMCID: PMC6735613
PMID: 30657523
Abstract
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.
Details
- Title: Subtitle
- VCAN Canonical Splice Site Mutation is Associated With Vitreoretinal Degeneration and Disrupts an MMP Proteolytic Site
- Creators
- Peter H Tang - Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United StatesGabriel Velez - Medical Scientist Training Program, University of Iowa, Iowa City, Iowa, United StatesStephen H Tsang - 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 StatesAlexander G Bassuk - Department of Pediatrics, University of Iowa, Iowa City, Iowa, United StatesVinit B Mahajan - Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States
- Resource Type
- Journal article
- Publication Details
- Investigative ophthalmology & visual science, Vol.60(1), pp.282-293
- Publisher
- United States
- DOI
- 10.1167/iovs.18-25624
- PMID
- 30657523
- PMCID
- PMC6735613
- ISSN
- 0146-0404
- eISSN
- 1552-5783
- Grant note
- T32 GM007337 / NIGMS NIH HHS
- Language
- English
- Date published
- 01/02/2019
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984070988202771
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