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K. Ray, M. Acharya, S. Mookherjee, A. Bhattacharjee, D. Banerjee; Potential Functional Role of CYP1B1 in POAG Pathogenesis. Invest. Ophthalmol. Vis. Sci. 2009;50(13):899.
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Primary Open Angle Glaucoma (POAG) is the most common of the glaucoma subtypes. CYP1B1 defects, despite causing primary congenital glaucoma, have also been implicated in POAG. It has been suggested that mutation in CYP1B1 causes POAG by a digenic mode of inheritance together with MYOC defect. To explain the basis of digenic POAG, we hypothesize that 17β estradiol can induce MYOC expression through the putative EREs (estrogen response elements) located in its promoter and CYP1B1 could manipulate MYOC expression by converting 17β estradiol into 4-hydroxy estradiol, thus preventing it from binding to MYOC promoter. Hence any mutation in CYP1B1 that reduces its enzymatic activity has the potential to induce glaucoma pathogenesis by over expression of MYOC.
Promoter region of Myocilin containing putative EREs was cloned into promoterless pGL3 vector containing luciferase reporter gene .The constructs were transfected in RPE cells followed by treatment with 17β estradiol. The mutant CYP1B1 clones were generated by site directed mutagenesis and the enzymatic activity of each mutant was measured by luciferase based assay. The expression of endogenous MYOC was analyzed in the background of the CYP1B1 mutants in TM cell line.
Consistent estradiol mediated induction was observed in the largest ‘MYOC promoter-pGL3 construct’ containing all 3 EREs as measured by luciferase assay. A few CYP1B1 alleles harboring missense changes, detected in POAG patients, were found to have 5-10% residual enzymatic activity compared to the wild type. When the level of endogenous MYOC expression was analyzed in the background of these CYP1B1 variants, a 50-80% increase in the MYOC expression was observed with respect to normal CYP1B1 in TM cell line.
Our result suggests that the ERE elements in the MYOC promoter are active and mutant CYP1B1 which lacks the 17β estradiol metabolizing activity can induce over expression of MYOC, thus contributing to the POAG pathogenesis.
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