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Christina Zeitz, Samuel Jacobson, Christian Hamel, Kinga Bujakowska, Marion Neuillé, Elise Orhan, Xavier Zanlonghi, Jose Sahel, Shomi Bhattacharya, Isabelle Audo, CSNB study group; Whole exome sequencing identifies mutations in LRIT3 as a cause for autosomal recessive complete congenital stationary night blindness. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3350.
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© ARVO (1962-2015); The Authors (2016-present)
Mutations in NYX, GRM6, TRPM1 and GPR179 expressed in ON-bipolar cells, lead to a disruption of the ON-bipolar response and reduced night vision. This dysfunction is present in patients with complete congenital stationary night blindness (cCSNB). Although many cases of cCSNB have been caused by mutations in these genes, in some of the patients the gene defect remains unknown. Here we sought to identify the disease-causing gene in the remaining patients by whole exome sequencing.
Whole exome sequencing was applied to one simplex cCSNB case lacking mutations in the known genes. Tissue specific and prediction databases were used to define the most promising candidate gene defect. In addition, Sanger sequencing in other CSNB patients was performed. RT and immunolocalization with confocal microscopy studies of the candidate gene were applied.
Whole exome sequencing led to the identification of a missense mutation (c.983G>A p.Cys328Tyr) and nonsense mutation (c.1318C>T p.Arg440*) in a gene LRIT3 coding for a Leucine-Rich Repeat (LRR), immunoglobulin-like and transmembrane domains 3 protein. Subsequent Sanger sequencing of 89 individuals with CSNB identified another cCSNB case harboring a nonsense mutation (c.1151C>G p.Ser384*) and a deletion (c.1538_1539del p.Ser513Cysfs*59) in the same gene. Human LRIT3 antibody staining revealed a punctate-labeling pattern in the outer plexiform layer of the human retina, resembling dendritic tips of bipolar cells as found in other proteins implicated in cCSNB.
Including the current study, mutations in five genes have been implicated in cCSNB. All localize postsynaptically to the photoreceptors in the retina in ON-bipolar cells. The mutation spectrum described here affect different domains of LRIT3, including the Cys328, which is predicted to form a disulfide bond in the Ig-like domain. The three other mutations represent two nonsense mutations and a frameshift mutation, which are located in the last exon. Thus it is most likely that mutant mRNA products escape nonsense-mediated decay. Further functional studies will eventually clarify the exact role and pathogenic mechanism of LRIT3 within the ON-bipolar cell pathway.
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