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Seyyedhassan Paylakhi, Cassandre Labelle-Dumais, Nicholas Tolman, Michael Sellarole, Piotr Topilko, Simon W John, Saidas Nair; Loss of Prss56 Function Contributes to Angle Closure Glaucoma-Relevant Phenotypes. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3685.
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© ARVO (1962-2015); The Authors (2016-present)
We have previously characterized an ENU-induced mutant mouse model that recapitulates features of angle closure glaucoma (ACG), which is estimated to affect 16 million people worldwide. The causal mutation was identified in the gene coding for serine protease Prss56. Prss56 mutant mice exhibit reduced ocular axial length and a relatively large lens, features that predispose the iris to be pushed forward causing blockage of the drainage structure (angle closure) and elevated intraocular pressure (IOP). Prss56 variants contribute to nanophthalmos and are associated with ACG in humans. None of the mutations reported to date completely disrupts the catalytic domain of Prss56. Thus, it is not clear if mutations in Prss56 act through their inability to cleave an endogenous substrate(s) or because they function in a promiscuous manner. Here, we utilized mice with a targeted Prss56 null mutation to determine if loss of Prss56 function leads to ACG-relevant phenotypes.
The Prss56 knockout mouse was generated by replacing Prss56 exon1 with the gene encoding Cre recombinase (Prss56-Cre). Mice lacking Prss56 are viable and fertile. Prss56 knockout and control littermates were assessed for angle closure glaucoma-relevant phenotypes. Slit-lamp biomicroscopy of eyes was performed at ages ranging from 1 to 8 months. IOP was measured at various ages within this range. Ocular dimensions were measured using a Vernier Caliper. Prss56-Cre mice were bred to a Rosa26-tdTomato reporter line to determine endogenous Prss56 expression in ocular tissues.
Prss56 knockout mice have significantly reduced ocular axial length with a normal occurring iris similar to that observed in ENU-induced Prss56 mutant mice (with an intact catalytic domain). However, the lens diameter of Prss56 knockouts was the same as that of the controls. Thus, the mutant lens occupies a larger ocular volume, a risk factor for ACG. Many Prss56 knockout mice also develop high IOP (>21 mmHg). Microscopic analysis of the Cre reporter mice demonstrates that Prss56 is predominantly expressed in the retina by a subpopulation of Muller cells.
Our results demonstrate that loss of Prss56 function contributes to ACG-relevant phenotypes, likely through its inability to process endogenous substrate(s). Current efforts focus on identifying endogenous Prss56 substrates.
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