We generated 6 transgenic lines with insertion of an expression plasmid for the R883/M xanthine dehydrogenase (XDH) mutant protein. Approximately 20% of the animals deriving from one of the transgenic lines show ocular abnormalities and an increase in intra-ocular pressure which are consistent with glaucoma. The observed pathologic phenotype is not due to expression of the transgene, but rather the consequence of the transgene insertion site, which has been defined by genome sequencing. The insertion site maps to chromosome 1qA3 in close proximity to the loci encoding AP-2β and AP-2δ, two proteins expressed in the eye. The insertion leads to a reduction in AP-2β and AP-2δ levels. Down-regulation of AP-2β expression is likely to be responsible for the pathologic phenotype, as conditional deletion of the Tfap2b gene in the neural crest has recently been shown to cause defective development of the eye anterior segment and early-onset glaucoma. In these conditional knock-out and our transgenic mice, the morphological/histological features of the glaucomatous pathology are surprisingly similar. Our transgenic mouse represents a model of angle-closure glaucoma and a useful tool for the study of the pathogenesis and the development of innovative therapeutic strategies.
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