Elucidation of function and role in retina pathophysiology of the G protein-coupled receptor GPR179 – GPR179

Night vision requires signaling from rod photoreceptors to adjacent bipolar cells in the retina. Mutations in the genes NYX, GRM6 and TRPM1, expressed by ON-bipolar cells, lead to a disruption of the ON-bipolar response. This dysfunction is present in patients with complete congenital stationary night blindness (CSNB) and can be assessed by standard full-field electroretinography (ERG), showing severely reduced rod b-wave amplitude and slightly altered cone responses. Although many cases of complete (c)CSNB have been caused by mutations in NYX, GRM6, and TRPM1 in ~20% of the patients the gene defect remains unknown. We applied whole exome sequencing in patients who had previously been excluded for mutations in known genes implicated in cCSNB and identified a homozygous missense mutation in one consanguineous arCSNB family and a homozygous frameshift mutation in a simplex male cCSNB patient from another consanguineous family in a new gene, GPR179. Additional screening using Sanger sequencing of 40 patients identified 3 other cCSNB cases harboring compound mutations in this gene. To date no article about this gene has been published. However, an EST profile is available and show expression in the human eye, heart and brain. Interestingly, the gene showed overexpression in the rd1-/- mouse starting from developmental stage d7 onwards, which increases in accordance with the photoreceptor cell degeneration in this mouse indicating inner retina expression. Indeed, by performing real-time PCR experiments and RNA in situ hybridization we confirmed retina and more precisely inner nuclear layer expression of Gpr179 in mouse. Immunolocalization studies performed with a commercially available antibody detected the antigen close to the outer plexiform layer (OPL) and in the inner limiting membrane (ILM), presumably concentrated in horizontal cells and Müller cell endfeet. Although, RNA in situ hybridization studies and immunohistological studies revealed inner retina localization of the respective Gpr179 transcript and protein, it did not co-localize with specific ON-bipolar markers, like the other proteins implicated in cCSNB.

With this project we propose to elucidate the role of this novel molecule in the retina and to investigate the pathogenic mechanism underlying cCSNB due to mutations in GPR179 by performing in vitro and in vivo experiments. These studies will further clarify the involvement of horizontal and Müller cells for the signaling from the photoreceptors to the adjacent bipolar cells in the retina.