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Igor E. Estrovich, Sunil Srivastava, Craig D. Beight, Stephanie A. Hagstrom; Genetic Analysis of Genes in the TLR Pathway in Patients with Acute Retinal Necrosis. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1573.
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: Acute retinal necrosis (ARN) and progressive outer retinal necrosis (PORN) are severe retinal infections caused by viruses in the herpes simplex family. Herpes simplex encephalitis has been reported to occur in some patients with ARN/PORN either simultaneously or subsequently to their retinal infection. The toll like receptors (TLR) play an important role in the natural immunity of humans especially in the defense to viral infections. Specifically, TLR3 deficiency has been described as a possible mechanism for herpes simplex encephalitis. Given the possible common mechanism of infection in patients with encephalitis and acute retinal necrosis, we sought to analyze patients with ARN for mutations in genes in the TLR pathway.
20 patients with acute retinal necrosis were identified. 14 of the 20 patients were PCR positive for herpes infection and of these, 7 also had a history of herpes associated encephalitis. Direct genomic sequencing of the entire coding region of TRL3 and UNC93B1 was performed. To date, a partial sequence analysis of STAT1 and NEMO has been performed. In silico analysis of identified sequence variants were evaluated using the PolyPhen-2 and PMut algorithms.
: Two isocoding changes (F459 and F851) and one missense change (L412F) were identified in TLR3. All three changes have been previously identified and L412F has been reported to impair function of the receptor. Five isocoding changes (A407, T484, R519, R525 and G590) and 10 missense changes (V499L, A506V, A508T, G516H, Y539D, Y539G, R540G, S547V, E555D and H556L) were identified in UNC93B1. Six of the 10 missense changes were identified in normal controls and the minor allele frequencies in our patients was not significantly different. Y539G, R540G and S547V were not found in normal controls and are predicted to be pathogenic by computational methods. Q516H was also not found in normal controls; however, this variant is predicted to be benign. To date, no sequence changes have been identified in STAT1 and NEMO.
We report one sequence variant in TLR3 and three sequence variants in UNC93B1 in patients with ARN that may impair function of the respective protein. Further experiments are ongoing to determine whether these confer susceptibility towards viral infection and subsequent disease. We are also proceeding with an evaluation of the remaining exons in STAT1 and NEMO.
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