Alteration of the serine protease PRSS56 causes angle-closure glaucoma in mice and posterior microphthalmia in humans and mice

Abstract

Angle-closure glaucoma (ACG) is a subset of glaucoma affecting 16 million people1–3. Although 4 million people are bilaterally blind from ACG4,5, the causative molecular mechanisms of ACG remain to be defined. High intraocular pressure induces glaucoma in ACG. High intraocular pressure traditionally was suggested to result from the iris blocking or closing the angle of the eye, thereby limiting aqueous humor drainage. Eyes from individuals with ACG often have a modestly decreased axial length, shallow anterior chamber and relatively large lens, features that predispose to angle closure6. Here, we show that genetic alteration of a previously unidentified serine protease alters axial length and causes a mouse phenotype resembling ACG. Mutations affecting this protease also cause a severe decrease of axial length in individuals with posterior microphthalmia. Together, these data suggest that alterations of this serine protease may contribute to a spectrum of human ocular conditions including reduced ocular size and ACG.

The genetic mechanisms of primary angle closure glaucoma

“…A novel serine protease-encoding gene (PRSS56) was identified in association with reduced axial length in a mouse model with an ACG-like phenotype. 93 Variations in PRSS56 were also found to cause significant reduction in the ocular axial length of individuals with posterior microphthalmia in the same study. In a recent GWA study of ACD and PACG in an Asian cohort, variants in the ATP-binding cassette, sub-family C (CFTR/MRP), and member 5 encoding gene (ABCC5) were found to influence ACD and increase the risk of PACG development.…”

Loss of Zebrafish Mfrp Causes Nanophthalmia, Hyperopia, and Accumulation of Subretinal Macrophages

“…45 It may be that the mechanism that prevents mouse Mfrp mutations from recapitulating human hyperopia does not affect eye size regulation at the same level as Prss56, because Prss56 mutants phenocopy human refractive error.…”

Genetics of Refraction and Myopia

“…Several loci for high hyperopia have been mapped, including NNO1 (OMIM 600165) at chromosome 11p for autosomal-dominant nanophthalmos, 6 MFRP of NNO2 (OMIM 606227) at chromosome 11q23.3 for autosomal-recessive nanophthalmos, 10 NNO3 (OMIM 611897) at chromosome 2q11-q14 for autosomal-dominant congenital simple microphthalmia, 11 TMEM98 of NNO4 (OMIM 615949) at chromosome 17p12-q12 for autosomaldominant nanophthalmos, 12,13 and PRSS56 (OMIM 613858) at chromosome 2q37.1 for autosomal-recessive posterior microphthalmos. 14,15 Families with physiologic high hyperopia are not uncommon, but the loci or genes responsible for them are yet to be identified.…”