Abstract
Congenital stationary night blindness (CSNB), in the complete form, is caused by dysfunctions in ON-bipolar cells (ON-BCs) which are secondary neurons of the retina. We describe the first disease causative variant associated with CSNB in the dog. A genome-wide association study using 12 cases and 11 controls from a research colony determined a 4.6 Mb locus on canine chromosome 32. Subsequent whole-genome sequencing identified a 1 bp deletion in LRIT3 segregating with CSNB. The canine mutant LRIT3 gives rise to a truncated protein with unaltered subcellular expression in vitro. Genetic variants in LRIT3 have been associated with CSNB in patients although there is limited evidence regarding its apparently critical function in the mGluR6 pathway in ON-BCs. We determine that in the canine CSNB retina, the mutant LRIT3 is correctly localized to the region correlating with the ON-BC dendritic tips, albeit with reduced immunolabelling. The LRIT3-CSNB canine model has direct translational potential enabling studies to help understand the CSNB pathogenesis as well as to develop new therapies targeting the secondary neurons of the retina.
Highlights
Our ability to visually perceive the surrounding environment is a result of the concerted action of multiple specialized cell types in the retina
Genetic variants that can cause complete Congenital stationary night blindness (CSNB) have been found in NYX17,18, GRM619, TRPM120,21, GPR17922,23, and LRIT324, whose protein products all localize to the dendritic tips of the ON-bipolar cells (ON-bipolar cells (BCs))
Since the CSNB allele was introduced in the research colony by a common founder, we hypothesized that the affected animals would be identical by descent (IBD) for the causative genetic variant as well as for the flanking chromosomal segments
Summary
Our ability to visually perceive the surrounding environment is a result of the concerted action of multiple specialized cell types in the retina. Once the photoreceptors capture light energy, the information is converted into neural signals that are relayed to multiple types of bipolar cells (BCs) that in turn transmit the signal to tertiary retinal neurons such as amacrine and retinal ganglion cells, before being transmitted to the visual cortex. Www.nature.com/scientificreports in the Riggs form due to defects in the photoreceptors[4], and is linked to variants in genes underlying proteins involved in rod phototransduction. It has both autosomal dominant (RHO, PDE6B and GNAT1) and recessive (SLC24A1 and GNAT1) inheritance[5,6,7,8,9,10]. Of the 30+ canine inherited retinal disease models whose causative genetic variants have been identified to date, the clinically-relevant canine LRIT3-CSNB is the only model with ON-BC defects and carries unique translational potential in therapeutic targeting of these secondary retinal neurons
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