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Christina Zeitz, Kinga Bujakowska, Elise Orhan, Jose-Alain Sahel, Shomi S. Bhattacharya, Isabelle Audo, CSNB study group; Mutations In A Novel Gene, GPR179 Lead To Autosomal Recessive Complete Congenital Stationary Night Blindness. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1729.
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Mutations in the genes NYX, GRM6 and TRPM1, expressed in ON-bipolar cells, lead to a disruption of the ON-bipolar response and subsequently night blindness. This dysfunction is present in patients with complete congenital stationary night blindness (cCSNB), a very significant human disease. Although many cases of complete CSNB are caused by mutations in NYX, GRM6 and TRPM1, in ~20% of the patients the genetic defects remain unknown. Here we sought to identify disease-causing mutations in the remaining patients by whole exome sequencing.
Whole exome sequencing was applied to two affected siblings and the parents of one consanguineous autosomal recessive family and one simplex patient with cCSNB previously excluded for mutations in NYX, GRM6 and TRPM1 by Sanger sequencing. Transcriptomic, tissue specific and prediction databases were used to define the most promising candidate gene. In addition, Sanger sequencing in other CSNB patients was performed. Real time PCR, RNA in situ hybridization and immunolocalization studies by confocal microscopy were used to localize the respective transcript and protein. 3D-modelling was performed to predict the pathogenic influence of the missense mutations.
Whole exome sequencing led to the identification of a homozygous missense mutation (c.1807C>T, p.His603Tyr) and a homozygous frameshift mutation (c.278delC, p.Pro93Glnfs*57) in a novel gene, GPR179. Screening using Sanger sequencing of 40 patients identified 3 additional cCSNB cases harboring compound heterozygous mutations in this gene. The gene is predicted to code for a G-protein coupled orphan receptor. The identified missense mutations may alter ligand binding. GPR179 is expressed in the inner retina and the respective protein is predominantly located in horizontal and Müller cells.
Our studies identified a novel gene, GPR179 that is associated with cCSNB. Although, RNA in situ hybridization and immunohistological studies revealed inner nuclear layer and outer plexiform layer localization of the respective Gpr179 transcript and protein, it seems not to co-localize with specific ON-bipolar markers, but with horizontal and Müller cells. The involvement of these cells in cCSNB and the specific function of this novel gene remain to be elucidated.
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