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K S. Nair, Zain Ali, Alison Kearney, Mihai Cosma, Gareth R. Howell, Richard Smith, Simon W. John; Grm4 Mutant Mice Are A Model For Angle Closure Glaucoma. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5919.
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© ARVO (1962-2015); The Authors (2016-present)
Angle closure glaucoma (ACG) is a subset of glaucoma affecting 16 million people worldwide. High intraocular pressure (IOP) induces retinal ganglion cell death and optic nerve atrophy in ACG. Eyes with ACG often have a modestly decreased axial length, shallow anterior chamber, and relatively large lens, features that predispose to angle closure. Reduced ocular dimensions alone are not sufficient to elevate IOP and other unknown physiological factors are thought to be important. The molecular mechanisms that underlie ACG are not clear. We have identified an ENU-induced mouse mutant (Glaucoma relevant mutant 4 - Grm4) that has increased lens to ocular volume and a phenotype-resembling ACG.
An ENU based, phenotype-driven, recessive screen was performed to detect mutant mice with high IOP. Slit-lamp biomicroscopy and histology were used to examine the eyes of Grm4 mutants ranging from 1 to 20 months of age. IOP was measured at various ages within this range. Retinal ganglion cell death and optic nerve degeneration was assessed by histological examination. Ocular dimensions were measured using a vernier caliper. Angles were assessed by gonioscopy and optical coherence tomography (OCT, Bioptigen). Gene mapping studies were performed to identify the mutation underlying the phenotype.
Grm4 mutants develop high IOP and have reduced outflow facility (∼ 50% IOP ≥ 19 mmHg at 3 months, ∼ 90% at 12 months). Histological analysis shows that the angles have a well-formed trabecular meshwork and Schlemm’s canal. Gonioscopy and OCT detected abnormally narrow angles in vivo. Pupillary dilation acutely raises IOP and results in anterior chamber deepening. Together, these data provide evidence for angle-closure. Subsequent to IOP elevation, some Grm4 mutants develop glaucomatous neurodegeneration. Measurements of enucleated eyes demonstrate variable reduction of ocular size (modest to severe, depending on genetic background). On a C57BL/6J background, adult mutant eyes have modestly reduced axial length (average 4.4 % smaller). Their lens dimensions are the same as control, however, reflecting increased lens to ocular volume as occurs in many ACG patients. We have genetically mapped Grm4 to chromosome 1 and are working to understand causative molecular mechanisms.
Grm4 mutant mice provide a much-needed animal model of ACG.
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