Purpose: Complete congenital stationary night blindness (CSNB1) is characterized by loss of night vision due to a defect in the retinal ON-bipolar cells (BCs). Mutations in GPR179, encoding the G-protein-coupled receptor 179, have been found in CSNB1 patients. In the mouse, GPR179 is localized to the tips of ON-BC dendrites. In this study we determined the ultrastructural localization of GPR179 in human retina and determined the functional consequences of mutations in GPR179 in patients and mice.
Methods: The localization of GRP179 was analyzed in postmortem human retinas with immunohistochemistry. The functional consequences of the loss of GPR179 were analyzed with standard and 15-Hz flicker ERG protocols.
Results: In the human retina, GPR179 is localized on the tips of ON-BC dendrites, which invaginate photoreceptors and terminate juxtaposed to the synaptic ribbon. The 15-Hz flicker ERG abnormalities found in patients with mutations in GPR179 more closely resemble those from patients with mutations in either TRPM1 or NYX than in GRM6. 15-Hz flicker ERG abnormalities of Gpr179(nob5) and Grm6(nob3) mice were comparable.
Conclusions: GRP179 is expressed on dendrites of ON-BCs, indicating that GRP179 is involved in the ON-BCs' signaling cascade. The similarities of 15-Hz flicker ERGs noted in GPR179 patients and NYX or TRPM1 patients suggest that the loss of GPR179 leads to the loss or closure of TRPM1 channels. The difference between the 15-Hz flicker ERGs of mice and humans indicates the presence of important species differences in the retinal activity that this signal represents.
Keywords: CSNB1; G-protein–coupled receptor; GPR179; missense mutations; pathogenicity; trafficking defect.