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Shan Gao, Tatjana C Jakobs; Mice homozygous for a deletion in the glaucoma susceptibility locus INK4 show increased vulnerability of retinal ganglion cells to elevated intraocular pressure. Invest. Ophthalmol. Vis. Sci. 2016;57(12):809.
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Several genome-wide association studies show that IINK4 locus on chromosome 9p21 is associated with primary open angle glaucoma and normal tension glaucoma. However, the mechanism is not yet clear. We hypothesize that genetic variants in this region may primarily impact optic nerve susceptibility in glaucoma.
We used 3-5 months old transgenic mice with a 70 kb-deletion of murine chromosome 4(Chr4Δ70kB/Δ70kB), syntenic to human chromosome 9p21, to test whether the deletion of parts of CDKN2B-AS (AK148321) leads to discernible phenotype in ocular structures implicated in glaucoma, including the anterior eye, retina and optic nerve head, both morphologically and functionally. In addition we tested whether mice homozygous for this deletion show increased susceptibility to elevated intraocular pressure, induced by an injection of microbead into the anterior chamber.
Homozygous mutant mice of this strain have been reported to show a phenotype resembling persistent hyperplastic primary vitreous. Our results of slit lamp, fundus photography and optical coherence tomography confirmed that finding but showed no abnormalities for heterozygous mice. Optokinetic response, eletroretinogram and histology indicated that the heterozygous and mutant retinas were normal functionally and morphologically, while glial cells were activated in the retina and optic nerve head of mutant eyes. In quantitative PCR, CDKN2B expression was reduced by about 50% in the heterozygous mice and by 90% in the homozygous mice. In elevated intraocular pressure eyes, induced by microbead injection, retinal ganglion cell loss, ganglion cell function loss, and optic nerve pathology were significantly worse in the homozygous mice compared to wild-type and heterozygous mice. This was accompanied by stronger microglia activation.
Phenotypic analysis indicate that neither the partial deletion of AK148321 nor the down-regulation of CDKN2B has a significant negative effect on neural retina anatomy and function of heterozygous and homozygous eyes under normal conditions. Our results are consistent with the hypothesis that mutations in the glaucoma susceptibility locus on chromosome 9p21 predisposes to increased vulnerability of ganglion cells to intraocular pressure at least partly by a stronger activation of microglia in the retina and optic nerve.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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