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John Kuchtey, Jessica Kunkel, Monique Michelle McCallister, John M Scichilone, Rachel W Kuchtey; Low tension glaucoma in microfibril deficient mice. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3804.
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© ARVO (1962-2015); The Authors (2016-present)
Based on our previous identification of a mutation in a microfibril-associated gene in a dog model of glaucoma, we formed the hypothesis that glaucoma may be caused by microfibril defects. To test this hypothesis, we have characterized glaucoma phenotypes in 2 lines of mice with established microfibril deficiencies due to mutations in the fibrillin-1 gene (Fbn1).
Comparisons were made between mice heterozygous for Fbn1 mutations and homozygous normal littermate controls. One mouse line carried a targeted C1039G mutation while the other carried the tight skin mutation (Tsk) of Fbn1. Outflow facility of enucleated mouse eyes was evaluated by constant pressure perfusion. Intraocular pressure (IOP) was measured by tonography of isoflurane anesthetized mice using the TonoLab instrument. Central corneal thickness of intact eyes was determined by spectral domain optical coherence tomography (SD-OCT). Retinal ganglion cell (RGC) numbers were determined by counting Brn3a-stained retinal whole mounts. Ganglion cell complex thickness was determined by SD-OCT imaging of the retina.
Microfibril deficient mice had decreased outflow facility with a 48% reduction for Fbn1C1039G/+ mice and 77% reduction for Tsk+/- mice, compared to wild type controls (p<0.05). The central cornea was >20% thinner in microfibril deficient as compared to controls (p<0.001). Despite decreased outflow facility, IOP was similar to (Tsk+/- mice), or less than (Fbn1C1039G/+ mice, p<0.01), IOP of controls. Calibration of the tonometer was not affected by the thin corneas of microfibril deficient mice. Glaucomatous RGC degeneration was apparent in microfibril deficient mice as evidenced by lower RGC counts in Tsk+/- mice and thinner ganglion cell complex in Fbn1C1039G/+ mice as compared to controls.
Consistent with our microfibril hypothesis of glaucoma, microfibril deficiencies were associated with glaucoma phenotypes in 2 separate lines of mice with mutations in Fbn1. Lower outflow facility did not result in higher IOP, suggesting a compensatory mechanism affecting aqueous humor turnover. Lower RGC counts and thinner ganglion cell complex in microfibril deficient mice with normal or low IOP suggests that microfibril deficient mice may be the first animal model of low tension glaucoma.
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