Byers Eye Institute, Omics Laboratory, Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, California, United States.
Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States.
Invest Ophthalmol Vis Sci. 2019 Jan 2;60(1):282-293. doi: 10.1167/iovs.18-25624.
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.
为了深入了解玻璃体视网膜变性的病理生理学，描述了三例黏连蛋白玻璃体视网膜病变（VVR）患者的临床病程，并对编码黏连蛋白（VCAN）蛋白的基因中的一个典型剪接位点突变进行了生化分析。
进行了回顾性图表审查、人眼组织病理学、Sanger DNA 测序、蛋白质结构建模和体外蛋白水解试验。
先证者（II:1）、母亲（I:2）和弟弟（II:2）患有视网膜变性伴黄斑保留和视网膜脱离伴增生性玻璃体视网膜病变，组织病理学分析证实了这些特征。所有受影响的成员都携带杂合腺嘌呤到鸟嘌呤变异（c.4004-2A>G），预测会导致 8 号外显子跳过或 GAGβ链（VCAN p.1335-1347）起始处的 13 个氨基酸缺失。该缺失区域对应于一个假定的 MMP 切割位点，使用荧光共振能量转移（FRET）基于蛋白水解试验进行了验证。蛋白质组网络分析鉴定了人类玻璃体和视网膜中与视网膜脱离和变性相关的 10 个相互作用的伴侣。
VVR 导致严重的眼部疾病，包括视网膜脱离和视网膜营养不良。VCAN 基因中的内含子突变去除了一个 MMP 切割位点，改变了黏连蛋白的结构，导致异常的玻璃体建模。黏连蛋白蛋白网络的破坏可能是临床病理疾病特征的基础，并指向靶向治疗。
