PRSS56 is required for the developmental positioning of ocular angle structures

Abstract

Angle-closure glaucoma (ACG) is a severe form of glaucoma affecting up to 16 million people worldwide. In ACG, physical blockage of the ocular drainage tissue by the peripheral iris impedes the drainage of aqueous humor resulting in elevated intraocular pressure (IOP) and subsequent optic nerve damage. Despite the high prevalence of ACG, the precise mechanism(s) underlying pathogenesis are only partially understood. We have previously demonstrated that a mutation in the gene encoding the serine protease PRSS56 causes an ACG phenotype in mice. Notably, Prss56 mutant mice exhibit a reduced ocular axial length and a lens occupying a larger ocular volume compared to WT mice, recapitulating characteristic features of human AGC. Our findings utilizing mouse genetic models demonstrate that loss of PRSS56 function results in altered configuration of ocular angle structures characterized by a posterior shift in the positioning of the ocular drainage tissue relative to the ciliary body and iris during development, leading to a physical blockage of drainage structure (angle closure) and high IOP. Utilizing a previously employed genetic strategy of rescuing mutant Prss56 mediated reduction in ocular size by inactivation of EGR1 (Egr1;Prss56 double mutants) we determined the influence of ocular size on developmental positioning of the ocular angle tissues. Our findings suggest that abnormal positioning of the drainage structure as a result of loss of PRSS56 function is uncoupled from its effect on ocular axial length reduction. Furthermore, we demonstrate that the IOP elevation observed in Prss56 mutant mice is genetic context-dependent and identify a dominant modifier locus on Chromosome 2 of the C3H/HeJ genome conferring susceptibility to high IOP. Overall, our findings reveal a novel role for PRSS56 in the proper configuration of the iridocorneal angle and provide new insight into the developmental pathways implicated in glaucoma pathogenesis.