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Frances E. Cone, Cathy Nguyen, Matthew Steinhart, Thao Nguyen, Mary Pease, Oliver Puk, Jochen Graw, Ericka Oglesby, Harry Quigley; Mice with an Induced Mutation in Collagen 8A2 Exhibit Axial Elongation and Are Resistant to Retinal Ganglion Cell Damage in an Experimental Glaucoma Model. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1748.
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To identify changes in sclera connective tissue that influence susceptibility to glaucoma injury.
Mice homozygous for an N-ethyl-N-nitrosourea induced G257D exchange (Gly to Asp) missense mutation in their collagen 8A2 gene (Puk et al, IOVS 2009) were studied for: intraocular pressure (IOP), axial length, number of retinal ganglion cells (RGC), and inflation testing (Myers et al, Exp Eye Res 2010). Collagen 8 is expressed in both cornea and sclera, and this line demonstrates a thinner than normal cornea. Homozygous Aca23 mutant and matched wild type (WT) 3 month old mice had 6 weeks exposure to elevated IOP induced by polystyrene bead injection (Cone et al, Exp Eye Res 2010).
Aca23 mice had significantly longer eyes than WT mice at 3 ages (4 mo: 3.81 vs 3.53mm, 10 mo: 3.90 vs 3.55mm; 18 mo: 4.2 vs 3.6mm (all p<0.0001, 20-30 eyes/group). Baseline IOP (4 mo olds) was 14.6 + 0.1mmHg (Aca23) and 15.3 + 1.1mmHg (WT), 4 measures/eye, 30 eyes/group, p=0.01. Baseline RGC axon counts (4 mo olds) were similar in Aca23 and WT (46,905 + 7,592 vs 43,628 + 11,162; n=37, 29; p=0.2). With inflation testing, the posterior sclera of Aca23 eyes had significantly less meridional and circumferential strain than WT (4-6 months old; n=29, 22; p <0.003), as well as significantly lower circumferential stress resultant (p=0.006). After bead-induced glaucoma, both Aca23 and WT eyes elongated, with similar final mean axial length (Aca23: 4.15 + 0.26 mm, WT: 4.05 + 0.24 mm; n=37, 30; p=0.1), but the absolute and percent change in both axial length and width from baseline was significantly less in Aca23 eyes (8% vs 13% in WT, p=0.01). Aca23 eyes had slightly higher IOP exposure than WT comparing each to fellow, uninjected control eyes (positive integral IOP: 108.5 (Aca23) vs 87.6 mmHg-days (WT); p=0.2). Aca23 eyes lost almost no RGC compared to WT. Mean axon loss was 0.6% in Aca23 vs. 21.1% in WT (p =0.005, multivariable regression, adjusting for IOP exposure).
This is the first identification of a gene mutation leading to altered (improved) susceptibility in experimental glaucoma. Detailed study of the specific alterations in scleral connective tissue composition and behavior that are favorably altered in this strain could produce new therapeutic targets for RGC neuroprotection.
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