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Rohit Agarwal, Kuldeep Mohanty, Swetasmita Mishra, Dileep Kumar, Rima Dada, Dewang Angmo, Tanuj Dada; Genetic screening & oxidative stress analysis in primary open angle glaucoma (POAG). Invest. Ophthalmol. Vis. Sci. 2014;55(13):2143.
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To evaluate the mutation spectrum in all candidate genes and perform whole mitochondrial DNA analysis in North Indian Primary Open Angle Glaucoma and correlate these with oxidative stress.
The study included 54 POAG patients & 50 controls. MYOC, NTF4 & WDR36 genes were amplified by PCR. Mitochondrial genome was screened in cases negative for any changes in the candidate genes. Reactive oxygen species (ROS) levels were measured by chemiluminescence method & total antioxidant capacity (TAC) was measured by ELISA. Microarray analysis was done by Agilent human whole genome oligo microarrays. Significantly differentially expressed genes were validated by real time PCR.
Twenty six cases (48.2%) had a pathogenic nucleotide change in exon 1 of MYOC (G887A) corresponding to amino acid change p.R76K . None of the controls presented these changes. Total of 156 (in patients) & 79 (in controls) mtDNA nucleotide variations were found in this study. Five pathogenic changes (3 novel & 2 reported) were found. Complex I had highest number of non synonymous changes. Blood ROS levels were significantly higher (p=0.03) & TAC levels significantly lower (p<0.001) in patients as compared to controls. There was a positive correlation (r=0.79, p=0.0001) & a strong negative correlation (r=-0.89, p=0.0001) of total number of mtDNA nucleotide changes in coding region with ROS levels & TAC levels respectively. We found 380 dysregulated genes in POAG cases. Major pathways involved were cell adhesion-ECM remodeling, IL1 signaling & cytoskeletal remodelling.
Nearly half of POAG cases had mutations in exon 1 of MYOC. Mitochondrial nucleotide changes lead to oxidative stress in POAG. The pathways involving the dysregulated genes are the ones mainly involved in the maintainance of Trabecular Meshwork integrity & structure.
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