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Glaucoma is a leading cause of irreversible vision loss due to retinal ganglion cell (RGC) degeneration that develops slowly with age. Elevated intraocular pressure (IOP) is a significant risk factor, although many patients develop glaucoma with IOP in the normal range. Mutations in microfibril-associated genes cause glaucoma in animal models, suggesting the hypothesis that microfibril defects contribute to glaucoma. To test this hypothesis, we investigated IOP and functional/structural correlates of RGC degeneration in mice of either sex with abnormal microfibrils due to heterozygous Tsk mutation of the fibrilin-1 gene ( Fbn1 Tsk   /+ ). Although IOP was not affected, Fbn1 Tsk   /+ mice developed functional deficits at advanced age consistent with glaucoma, including reduced RGC responses in electroretinogram (ERG) experiments. While RGC density in the retina was not affected, the density of RGC axons in the optic nerve was significantly reduced in Fbn1 Tsk   /+ mice. However, reduced axon density correlated with expanded optic nerves, resulting in similar numbers of axons in Fbn1 Tsk   /+ and control nerves. Axons in the optic nerves of Fbn1 Tsk   /+ mice were significantly enlarged and axon diameter was strongly correlated with optic nerve area, as has been reported in early pathogenesis of the DBA/2J mouse model of glaucoma. Our results suggest that microfibril abnormalities can lead to phenotypes found in early-stage glaucomatous neurodegeneration. Thinning of the elastic fiber-rich pia mater was found in Fbn1 Tsk   /+ mice, suggesting mechanisms allowing for optic nerve expansion and a possible biomechanical contribution to determination of axon caliber.

Enlarged Optic Nerve Axons and Reduced Visual Function in Mice with Defective Microfibrils