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RR Dubielzig, K O'Leary, A Shen, CB Kasper; Enhanced Expression of Congenital Glaucoma with Features of Posterior Polymorphous Dystrophy in NADPH-cytochrome P450 Oxidoreductase-deficient Mice . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3378.
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Purpose: To characterize the morphology and inheritance of ocular disease presenting as ocular enlargement in transgenic mice derived from R1 embryonal stem cells heterozygous for a disrupted NADPH-cytochrome P450 oxidoreductase (CYPOR) gene and enhancement of this syndrome by CYPOR deficiency. Methods: This colony of mice is derived from R1 embryonal stem cells heterozygous for a disrupted CYPOR gene which is unable to support microsomal P450-dependent activities. Enzymatic activity in liver microsomes is 60% of wild type. CYPOR +/- mice are maintained on a 129/C57BL6 background. Affected mice have visible enlargement of the cornea apparent as early as 35 days. Plastic sections for light and transmission electron microscopy were done on one CYPOR +/+ (wild-type) unaffected eye, one wild-type affect eye, and one CYPOR +/- (heterozygous) affected eye. Results: By observation of 300 mice, 14% of CYPOR +/+ mice and 21% of CYPOR +/- mice are affected. Abnormal eyes have deepened anterior chambers which extend to the level of the ora serata. Affected mice have an abnormal accumulation of cells seen first in the iridocorneal angle and spreading along the iris surface and across the posterior cornea with disease progression. Abnormal cells have epithelial features characterized by kytokeratin expression and surface microvilli. Conclusions: An apparently congenital glaucoma characterized by corneal enlargement, deepening of the anterior chamber , and epithelialized trabecular lining cells is reported. Congenital glaucoma has not been reported in 129 or C57 mice. We believe that this phenotype arose in the R1 embryonal stem cell clone used to produce these transgenic mice. The pathway(s) affected by this unknown mutation may involve CYPOR since deficiency of CYPOR results in a small enhancement. Deficiency of cytochrome P450 1B1 is thought to be involved in human congenital glaucoma but epithelialization of trabecular lining cells or endothelial cells is reported as a feature of posterior polymorphous corneal dystrophy.
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