Vitreoretinopathy, Neovascular Inflammatory

A number sign (#) is used with this entry because of evidence that neovascular inflammatory vitreoretinopathy (VRNI) is caused by heterozygous mutation in the CAPN5 gene (602537) on chromosome 11q14.

Description

Autosomal dominant neovascular inflammatory vitreoretinopathy is a blinding disorder that shares some clinical features with retinitis pigmentosa (see 268000), uveitis, and proliferative diabetic retinopathy (see 603933). Features include prominent ocular inflammation; vascular dropout, large spots of hyperpigmentation, and neovascularization of the peripheral and posterior retina; vitreous hemorrhage; and retinal detachment (summary by Sheffield et al., 1992).

Clinical Features

Bennett et al. (1990) studied a large 6-generation family of northern European ancestry segregating autosomal dominant inflammatory eye disease. There were 28 affected individuals, the condition was present in every generation, and there was at least 1 documented male-to-male transmission. The youngest age at which symptoms developed was 16 years; most affected individuals remained asymptomatic until their third or fourth decade. The first signs of disease included vitreous cells, minimal far-peripheral arteriolar closure and pigmentation, and selective reduction in the b-wave of the electroretinogram (ERG). In middle age, more prominent anterior and posterior inflammation, progressive vascular closure with neovascularization of the far peripheral retina or optic disc, vitreous hemorrhage, tractional retinal detachment, fluorescein leakage in the posterior pole and midperiphery, and cystoid macular edema develop. By 60 years of age, cataracts, marked progressive neovascularization, and tractional retinal detachment were observed, and anterior segment neovascularization developed. Cystoid macular edema, vitreous hemorrhage, tractional retinal detachment, and neovascular glaucoma caused profound visual loss in some patients. The ERG was extinguished late in the disease.

Mahajan et al. (2012) studied 2 families segregating autosomal dominant neovascular inflammatory vitreoretinopathy and noted that the phenotype was very similar to that described by the pedigree described by Bennett et al. (1990). Affected members exhibited noninfectious uveitis, early loss of the b-wave on electroretinography, pigmentary retinal degeneration, cystoid macular edema, retinal and iris neovascularization, vitreous hemorrhage, epiretinal membrane formation, proliferative vitreoretinopathy, retinal detachment, cataract, neovascular glaucoma, and ultimately phthisis and complete blindness. Both pedigrees were consistent with autosomal dominant inheritance with complete penetrance.

Mapping

Sheffield et al. (1992) established close linkage of VRNI to markers that map to 11q13. In a single large pedigree, linkage analysis with the closest marker, D11S527, demonstrated a maximum lod of 6.29 with no recombinants. Stone et al. (1992) reported that they had found 34 affected members in this pedigree, that no recombinants were found between the disease phenotype and D11S527, and that multipoint analysis yielded a maximum lod score of 11.9 centered on this marker. Another inherited retinal dystrophy, Best macular dystrophy (VMD; 153700), also maps to 11q13. However, Sheffield et al. (1992) stated that the 2 diseases appear to be at least 10 cM apart.

Mahajan et al. (2012) genotyped 2 unrelated families segregating autosomal dominant neovascular inflammatory vitreoretinopathy and confirmed linkage to the 11q13 locus. Haplotype analysis was suggestive of an ancestral relationship between 1 of the families (ADNIV-2) and the original (ADNIV-1) family described by Bennett et al. (1990). Recombination events in 1 of the families (ADNIV-3) narrowed the critical interval to 6.5 Mb between D11S4139 and D11S1789; high resolution SNP genotyping of ADNIV-1 and ADNIV-3 further reduced the interval to 6 Mb between SNP rs879380 and D11S1789.

Pathogenesis

Proliferative vitreoretinopathy is characterized by the development of epi- and subretinal fibrocellular membranes containing modified retinal pigment epithelial (RPE) cells among others. Priglinger et al. (2003) found that tissue transglutaminase (190196) was present and functionally active in proliferative vitreoretinopathy membranes. The amount and activity of tissue transglutaminase appeared to be related to the differentiation state of the RPE cells and their stimulation by TGFB2 (190220), a growth factor known to be increased in the vitreous of proliferative vitreoretinopathy.

Molecular Genetics

Mahajan et al. (2012) performed whole-exome sequencing in the family with autosomal dominant neovascular inflammatory vitreoretinopathy originally reported by Bennett et al. (1990) (ADNIV-1) and identified a heterozygous missense mutation in the CAPN5 gene (R243L; 602537.0001) that segregated fully with disease. Sequencing of CAPN5 in 2 additional ADNIV families revealed that affected members of family ADNIV-2 carried the same heterozygous R243L mutation, whereas affected individuals from family ADNIV-3 were heterozygous for an adjacent missense mutation (L244P; 602537.0002). The mutations segregated with disease in each family and were not found in 272 ethnically matched controls or in the dbSNP or 1000 Genomes Project databases.

Animal Model

Saika et al. (2007) determined the effects of Smad7 (602932) gene transfer in the prevention of fibrogenic responses by the retinal pigment epithelium, a major cause of proliferative vitreoretinopathy after retinal detachment in mice. In a retinal detachment-induced proliferative vitreoretinopathy in a mouse model, Smad7 gene transfer inhibited TGFB2/Smad signaling in ARPE19 cells and expression of collagen type I and TGFB1 but had no effect on their basal levels. In vivo Smad7 overexpression resulted in suppression of Smad2/3 signals and of the fibrogenic response to epithelial-mesenchymal transition by the retinal pigment epithelium. Saika et al. (2007) concluded that Smad7 gene transfer suppressed fibrogenic responses to TGFB2 by retinal pigment epithelial cells in vitro and in vivo.

Wert et al. (2015) generated transgenic mice expressing human CAPN5(R243L) only in the retina and observed a clinical, histologic, and molecular phenotype consistent with human VRNI and uveitis. The fundi of the transgenic mice showed enhanced autofluorescence and pigment changes indicative of reactive retinal pigment epithelial cells and photoreceptor degeneration. Electroretinography of mutant mouse eyes revealed a selective loss of the b-wave, indicating an inner-retina signaling defect. Histologic analysis of mutant mouse eyes showed protein extravasation from dilated vessels into the anterior chamber and vitreous, vitreous inflammation, vitreous and retinal fibrosis, and retinal degeneration. Analysis of gene expression changes in the hCAPN5(R243L) mouse retina demonstrated upregulation of several markers, including members of the Toll-like receptor pathway, chemokines, and cytokines, indicative of both an innate and adaptive immune response. Noting that many forms of uveitis share phenotypic characteristics of VRNI, Wert et al. (2015) suggested that this mouse model might have therapeutic testing utility for VRNI and uveitis patients.