Congenital stationary night blindness (CSNB) is the clinical term for non-progressive retinal disorders that impair rod-mediated vision. The complete form of CSNB (cCSNB) is caused by defects in depolarizing bipolar cell (DBC) signal transduction and in patients has been linked to mutations in NYX, GRM6 or TRPM1. Because the flow of all visual input is transferred from the outer to the inner retina via bipolar cells, it is critical to understand the mechanism of signal transduction in DBCs. Recent work has defined several, but not all, players in this cascade. In this project, we will identify another key protein.
In Aim 1, we will identify the gene and mutation that underlies a new mouse model of DBC dysfunction, nob5. The nob5 gene locus is distinct from all other known models of DBC dysfunction and therefore its identification will add another protein to those known to be critical for DBC function. These studies will use next generation sequencing and positional cloning to map and clone the gene responsible for the nob5 phenotype.
In Aim 2, we will define the nob5 phenotype with respect to retinal function, using electroretinography and whole-cell patch clamp recordings from rod and cone DBCs and cone hyperpolarizing bipolar cells, and the morphology of the synapses between photoreceptors and DBCs, using confocal microscopy and immunohistochemistry. At the completion of this project, we will have identified a new protein that is required for normal DBC function and which can be used to screen patients with cCSNB.
This project will make detailed studies of a new mouse model (nob5) that lacks depolarizing bipolar cell (DBC) function. The nob5 gene has not been identified, but is known to involve a protein that has not been previously implicated in DBC function. Identification of the nob5 gene will expand our understanding of DBC signal transduction and will identify a potential new candidate gene for the complete form of human congenital stationary night blindness.
|Ray, Thomas A; Heath, Kathryn M; Hasan, Nazarul et al. (2014) GPR179 is required for high sensitivity of the mGluR6 signaling cascade in depolarizing bipolar cells. J Neurosci 34:6334-43|
|Klooster, Jan; van Genderen, Maria M; Yu, Minzhong et al. (2013) Ultrastructural localization of GPR179 and the impact of mutant forms on retinal function in CSNB1 patients and a mouse model. Invest Ophthalmol Vis Sci 54:6973-81|
|Peachey, Neal S; Ray, Thomas A; Florijn, Ralph et al. (2012) GPR179 is required for depolarizing bipolar cell function and is mutated in autosomal-recessive complete congenital stationary night blindness. Am J Hum Genet 90:331-9|