A Naturally Occurring Canine Model of Autosomal Recessive Congenital Stationary Night Blindness

Abstract

Congenital stationary night blindness (CSNB) is a non-progressive, clinically and genetically heterogeneous disease of impaired night vision. We report a naturally-occurring, stationary, autosomal recessive phenotype in beagle dogs with normal daylight vision but absent night vision. Affected dogs had normal retinas on clinical examination, but showed no detectable rod responses. They had “negative-type” mixed rod and cone responses in full-field ERGs. Their photopic long-flash ERGs had normal OFF-responses associated with severely reduced ON-responses. The phenotype is similar to the Schubert-Bornschein form of complete CSNB in humans. Homozygosity mapping ruled out most known CSNB candidates as well as CACNA2D4 and GNB3. Three remaining genes were excluded based on sequencing the open reading frame and intron-exon boundaries (RHO, NYX), causal to a different form of CSNB (RHO) or X-chromosome (NYX, CACNA1F) location. Among the genes expressed in the photoreceptors and their synaptic terminals, and mGluR6 cascade and modulators, reduced expression of GNAT1, CACNA2D4 and NYX was observed by qRT-PCR in both carrier (n = 2) and affected (n = 2) retinas whereas CACNA1F was down-regulated only in the affecteds. Retinal morphology revealed normal cellular layers and structure, and electron microscopy showed normal rod spherules and synaptic ribbons. No difference from normal was observed by immunohistochemistry (IHC) for antibodies labeling rods, cones and their presynaptic terminals. None of the retinas showed any sign of stress. Selected proteins of mGluR6 cascade and its modulators were examined by IHC and showed that PKCα weakly labeled the rod bipolar somata in the affected, but intensely labeled axonal terminals that appeared thickened and irregular. Dendritic terminals of ON-bipolar cells showed increased Goα labeling. Both PKCα and Goα labeled the more prominent bipolar dendrites that extended into the OPL in affected but not normal retinas. Interestingly, RGS11 showed no labeling in the affected retina. Our results indicate involvement of a yet unknown gene in this canine model of complete CSNB.

Characterization of a novel form of progressive retinal atrophy in Whippet dogs: a clinical, electroretinographic, and breeding study

“…Many of these are stationary conditions (congenital stationary night blindness: CSNB) that result from mutations in either genes encoding presynaptic photoreceptor proteins or in those expressed in the synaptic tips of bipolar cells. CSNB is well recognized in human ophthalmology and divided into different categories based on the details of the ERG and fundus changes . Several spontaneous and engineered mouse models have also been characterized and are commonly referred to as nob (no b‐wave) mice …”

“…Recently, a phenotype similar to the Schubert‐Bornschein form of complete CSNB in humans was described in Beagles and, despite screening candidate genes, the causal gene mutation was not identified . CSNB has been recognized for many years in the Appaloosa horse and more recently was shown to be due to a mutation in Trpm1 which encodes a channel protein important in bipolar cell function and melanocyte biology .…”

Variabilities in retinal function and structure in a canine model of cone-rod dystrophy associated with RPGRIP1 support multigenic etiology

“…The posterior eye cups were processed as previously described 31 . H&E-stained 10 µm sections from the superior quadrant were used to quantitate ONL and INL thickness (µm) and cell counts were indicated by rows of nuclei.…”

Presumed Photoreceptor Dysplasias in Peregrine Falcons (Falco Peregrinus) and Peregrine Falcon Hybrids

“…Negative ERGs reflect inner retinal dysfunction and, in humans, can be found in conditions such as congenital stationary night blindness, juvenile retinoschisis, fundus albipunctatus, Oguchi disease, diabetic retinopathy, rod-cone dysplasia, and some forms of retinal vascular disease (Nobel et al 1990;Audo et al 2007). Negative ERGs have also been shown to be associated with some forms of progressive retinal atrophy in dogs (Kondo et al 2015;Somma et al 2016). Electroretinograms dominated by the a-wave have also been described in early retinal degeneration in Norwegian elkhounds (Acland and Aguirre 1987).…”