A potential mouse model for the erosive vitreoretinopathy of Wagner disease      

Abstract

Patients with the very rare eye pathology Wagner disease (OMIM #143200) present with an abnormal (empty) vitreous, retinal detachment and altered electroretinogram (ERG). The disease is progressive and can eventually lead to blindness. No therapy can be offered to date. The genetic basis is the presence of mutations in the VCAN gene, encoding the large extracellular matrix molecule versican, which is a component of the vitreous. All identified mutations map to the canonical splice sites flanking exon 8, resulting in low number of aberrant splice products and a severe increase in two (V2, V3) of the four naturally occurring splice variants. The pathomechanism of Wagner's disease is poorly understood and a mouse model may afford further insight. The hdf -/-mice, named for their initial phenotype of heart defects, carry a null allele for Vcan that leads to embryonic lethality when homozygous, but heterozygote animals are viable. Here we investigated a possible eye phenotype in the heterozygous animals. While the overall morphology of retina and ciliary body appears to be normal, older (17 months) mutant animals show a decrease in ERG signalling profiles affecting the a-, b-and c-waves. This aspect of altered ERG profile demonstrates similarities to the human disease manifestation and underlines the suitability of heterozygous hdf +/-mice as a model for Wagner disease.

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

“…It is unclear whether additional bioactive fragments are generated. Although the mechanisms for versican processing in the eye are poorly understood, it is hypothesized that dysregulation of these pathways may result in pathologic matrix modeling in the vitreous 19,20. The role of versican in eye development is further supported by changes in VCAN protein expression in the developing mouse retina and optic nerve, although its significance remains to be delineated 21.…”

Controversy and Consideration of Refractive Surgery in Patients with Heritable Disorders of Connective Tissue

“…The prevalence is unknown, with an estimated total of 300 individuals affected [55]. The hallmark of Wagner Syndrome is an optically empty vitreous with avascular strands, membranes, or veils [16,54,78]. Other ocular features are myopia, night blindness from chorioretinal atrophy, presenile cataract, retinal detachment, and occasional uveitis beginning in adolescence (Table 3) [78].…”

“…The hallmark of Wagner Syndrome is an optically empty vitreous with avascular strands, membranes, or veils [16,54,78]. Other ocular features are myopia, night blindness from chorioretinal atrophy, presenile cataract, retinal detachment, and occasional uveitis beginning in adolescence (Table 3) [78]. In contrast to STL, no systemic abnormalities have been described.…”